CN108348580A

CN108348580A - The purposes of the inhibitor peptides of Interleukin-23 receptor and its treatment diseases associated with inflammation

Info

Publication number: CN108348580A
Application number: CN201680049562.2A
Authority: CN
Inventors: 格雷戈里·伯恩; 程晓力; 布莱恩·特洛伊·弗莱德里克; 张婕; 迪奈施·V·帕特尔; 刘永鸿; 艾少克·伯翰德瑞
Original assignee: Protagonist Therapeutics Inc
Current assignee: Protagonist Therapeutics Inc
Priority date: 2015-07-15
Filing date: 2016-07-15
Publication date: 2018-07-31
Anticipated expiration: 2036-07-15
Also published as: CN108348580B; CL2018000128A1; CR20180029A; IL256827A; PH12018500086A1; KR102513978B1; JP2018522008A; WO2017011820A2; CL2021000343A1; AU2016293619B2; EP3341011A4; KR20180030663A; EA035733B1; CL2018003322A1; EA035733B9; CA2991984A1; ECSP18002929A; MX2018000542A; PE20180571A1; DOP2018000010A

Abstract

The present invention is provided the novel inhibitor peptides of interleukin 23 receptor and relevant composition and is treated or prevented various diseases and illness using these inhibitor peptides, and the method for inflammatory bowel disease is included.

Description

The inhibitor peptides of Interleukin-23 receptor and its treat diseases associated with inflammation Purposes

Cross reference to related applications

This application claims the priority of the U. S. application submitted on July 15th, 2015 the 14/800,627th and it is its portion Point continuation application, and also require the International Patent Application PCT/US2015/040658 submitted on July 15th, 2015,2015 The U.S. Provisional Application No. submitted December 8 62/264,820 and the U.S. Provisional Application No. submitted on January 20th, 2016 62/281, No. 123 priority, it is all these to be incorporated herein by reference in their entirety.

Sequence table

The application includes the sequence table submitted with ASCII fromat electronics, and it is integrally incorporated this by reference Text.It is named as PRTH-002-03WO_SL.txt in the ASCII copies that on July 15th, 2016 creates and size is 504KB。

Invention field

The present invention relates to the novel inhibitor peptides of Interleukin-23 receptor and its treat or prevent a variety of diseases and The purposes of illness, the disease and illness include inflammatory bowel disease, Crohn disease and psoriasis.

Background

Interleukin-23 (IL-23) cell factor has been considered closing in such as multiple sclerosis, asthma, rheumatoid Section inflammation, psoriasis and inflammatory bowel disease (IBD), for example, the autoimmune inflammation and phase of ulcerative colitis and Crohn disease Decisive role is played in the pathogenesis of related disorders and illness.Research in the acute and chronic mouse model of IBD discloses The important function of IL-23R and downstream effect cell factor in disease pathogenesis.IL-23R is thin in a variety of adaptive immunities It is expressed on born of the same parents and inherent immunity cell, the cell includes that Th17 cells, gamma delta T cells, natural kill (NK) cell, dendron are thin Born of the same parents, macrophage and intrinsic lymphocyte, these cells largely exist in intestines.In intestinal mucosal surface, the base of IL-23R is found Because expression and protein level increase in IBD patient.Think that IL-23 generates IL-6, IL-17 and tumor necrosis factor by promotion (TNF) pathogenic CD4⁺The development of T cell group mediates the effect.

The IL-23 of generation is enriched in intestines, it is believed that, by helper T lymphocyte 1 (Th1) and Th17 relevant cells because The effect of son, and inhibit the regulatory T cells response (its be conducive to inflammation) in intestines, by T cell dependence and T cell it is non-according to The enteritis access of property is relied to play key effect in adjusting the balance between tolerance and immunity.In addition, IL-23 receptor (IL- Polymorphism 23R) is related to the neurological susceptibility to IBD, further establishes key effect of the IL-23 accesses in intestines stable state.

Have shown that psoriasis (chronic dermatosis for influencing the total population of about 2%-3%) is answered by internal T cell is inflammatory Mechanism is answered to mediate.IL-23 is one of several interleukins, it is considered to be pathogenetic pivotal player of psoriasis, according to Claim it via induction Interleukin-17, adjusting memory T cell and activated macrophage to maintain chronic auto-immune Inflammation.It has shown that the expression of IL-23 and IL-23R increase in the patient tissue with psoriasis, and neutralizes the anti-of IL-23 The IL-23 dependences that psoriasis develops in the animal model of body display psoriasis inhibit.

The heterodimer that IL-23 is made of the p40 subunits of unique p19 subunits and IL-12 is to participate in production interference 1 (the T of helper T lymphocyte of element-γ (IFN-γ)_H1) cell factor of development.Although it is sub- that IL-23 and IL-12 contain p40 Base, but they have different phenotypic characteristics.For example, IL-12 deficiency animals are susceptible to suffer from inflammatory autoimmune disease, and IL-23 deficiency animals are resistant, are because producing IL-6, IL-17 and TNF in the CNS of IL-23 deficiency animals by inference CD4⁺T cell number is reduced.IL-23 is combined with IL-23R, and the IL-23R is made of different IL-12R β 1 and IL-23R subunits Dimerization receptor body.Combination activation Jak-stat signal transducers Jak2, Tyk2 and Stat1, the Stat of IL-23 and IL-23R 3, Stat 4 and Stat 5, although the activation of Stat4 is substantially weaker, and when to IL-23 responses, compared to IL-12, shape At different DNA combination Stat compounds.Combine to IL-23R and Jak2 compositions, and in a manner of ligand-dependent with Stat3 is combined.Memorability CD4 (+) T is acted preferentially on compared to the IL-12 for mainly acting on initial CD4 (+) T cell, IL-23 Cell.

Inhibit the therapeutic moieties of IL-23 accesses in identification, has been done for treating the relevant diseases of IL-23 and illness aspect Effort is gone out.The lot of antibodies combined with IL-23 or IL-23R has been identified, including has been approved for the excellent for the treatment of psoriasis Special gram monoclonal antibody (ustekinumab) (in conjunction with the humanized antibody of IL-23).Recently, it has identified and has been combined and pressed down with IL-23R The peptide inhibitor that IL-23 processed is combined with IL-23R is (see, e.g., U.S. Patent Application Publication No. US2013/0029907 Number).With excellent spy gram monoclonal antibody and mine-laying slave monoclonal antibody (briakinumab) (it targets common p40 subunits) and What tildrakizumab, guselkumab, MEDI2070 and BI-655066 (it targets unique p19 subunits of IL-23) were carried out It is latent in treating people's diseases associated with inflammation that the clinical test of Crohn disease or psoriasis highlights the blocking of IL-23 signal transductions Energy.Although these are the discovery that promising, the stabilization of IL-23 accesses in intestines and selective medicine are preferentially targeted about identification Agent is still challenging, and the medicament can be used for treating enteritis, such as enteropathy, including Crohn disease, ulcerative colitis and phase Related disorders.

It is clearly that this field can be used for treating and preventing IL- there is still a need for the new treatment of targeting IL-23 accesses 23 relevant diseases include and the relevant disease of autoimmune inflammation in enteron aisle.In addition, selectively targeted come from enteric cavity side The Compounds and methods for of IL-23R can provide treatment benefit for the IBD patient with local intestinal tissue inflammation.The present invention is logical It crosses to provide in conjunction with IL-23R and be solved with the combination and signal transduction and the novel inhibitor peptides suitable for being administered orally that inhibit IL-23 These demands.

Summary of the invention

Present invention particularly provides the novel inhibitor peptides of IL-23R and relevant application methods.

In a first aspect, the present invention provides the inhibitor peptides or its pharmaceutically acceptable salt of Interleukin-23 receptor Or solvate, wherein the inhibitor peptides include the amino acid sequence of formula (Xa)：X1-X2-X3-X4-X5-X6-X7-X8-X9- X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Xa),

Wherein：

X1, X2 and X3 are arbitrary amino acid or are not present；

X4 is the arbitrary amino acid or chemical part that key can be formed with X9；

X5, X6, X7 and X8 are arbitrary amino acid；

X9 is the arbitrary amino acid or chemical part that key can be formed with X4；

X10, X11, X12, X13, X14 and X15 are arbitrary amino acid；And

X16, X17, X18, X19 and X20 are arbitrary amino acid or are not present；

The wherein described inhibitor peptides are cyclized via the key between X4 and X9, and

The wherein described inhibitor peptides inhibit the combination of Interleukin-23 (IL-23) and IL-23 receptor.

In certain embodiments of Xa：

X1 is not present；X2 is not present；X3 is not present；X4 is Cys, Abu or Pen；X5 be Ala, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn, Gln, Arg, Ser or Thr；X6 is Asp Or Thr；X7 is the chloro- Trp of Trp or 6-；X8 is Glu, Gln or Val；X9 is Cys, Abu or Pen；X10 is that 2-Nal, Phe are similar Object, Tyr or Tyr analogs；X11 is 1-Nal, 2-Nal, Phe (3,4- dimethoxy), 5- hydroxyls Trp, Phe (3,4-Cl₂)、 Trp or Tyr (3-tBu)；X12 is 3-Pal, Acpc, Acbc, Acvc, Achc, Agp, Aib, α-diethyl Gly, α-MeLys, α- MeLys(Ac)、α-MeLeu、α-MeOrn、α-MeSer、α-MeVal、Cav、Cha、Cit、Cpa、D-Asn、Glu、His、hLeu、 HArg, Lys, Leu, Octgly, Orn, 4- amino -4- Carboxy-piperidins, Arg, Ser, Thr or THP；X13 be Cit, Asp, Dab, Dap, Phe, His, Dap (Peg2-Ac), Dap (burnt glutaric acid), Glu, high Arg, Lys, Lys (Ac), Lys (benzoic acid), Lys (glutaric acid), Lys (IVA), Lys (the different Glu-Palm of Peg4-), Lys (burnt glutaric acid), Lys (succinic acid), Asn, Orn, Gln, Arg, Thr or Val；X14 be Asp, Dab (Ac), Dap (Ac), Phe, His, Lys (Ac), Met, Asn (isobutyl group), Gln, Arg, Tyr or Asp (1,4-Diaminobutane)；And X15 is Ala, β Ala, Glu, Gly, Asn, Gln, Arg or Ser.

In certain embodiments of Xa：X1 is not present；X2 is not present；X3 is not present；X4 is Cys, Abu or Pen；X5 is Ala, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, Orn, Gln, Arg, Ser or Thr；X6 is Asp or Thr；X7 is the chloro- Trp of Trp or 6-；X8 is Gln or Val；X9 is Cys, Abu or Pen；X10 is that 2-Nal, Phe are similar Object, Tyr or Tyr analogs；X11 is 1-Nal, 2-Nal, Phe (3,4- dimethoxy), 5- hydroxyls Trp, Phe (3,4-Cl₂)、 Trp or Tyr (3-tBu)；X12 is 3-Pal, Acpc, Acbc, Acvc, Achc, Agp, Aib, α-diethyl Gly, α-MeLys, α- MeLys(Ac)、α-MeLeu、α-MeOrn、α-MeSer、α-MeVal、Cav、Cha、Cit、Cpa、D-Asn、His、hLeu、 HArg, Lys, Leu, Octgly, Orn, 4- amino -4- Carboxy-piperidins or THP；X13 be Cit, Asp, Dab, Dap, Phe, His, Dap (Peg2-Ac), Dap (burnt glutaric acid), Glu, hArg, Lys, Lys (Ac), Lys (benzoic acid), Lys (glutaric acid), Lys (IVA), Lys (the different Glu-Palm of Peg4-), Lys (burnt glutaric acid), Lys- (succinic acid), Asn, Orn, Gln, Arg, Thr or Val；X14 is Dab (Ac), Dap (Ac), Phe, His, Lys (Ac), Met, Asn, Gln, Arg or Tyr；And X15 is Ala, β Ala, Gly, Asn, Gln or Ser.

In certain embodiments of Xa：X1 is not present；X2 is not present；X3 is not present；X4 is Cys, Abu or Pen；X5 is Dap, Dap (Ac), Gly, Lys, Gln, Arg, Ser, Thr or Asn；X6 is Thr；X7 is the chloro- Trp of Trp or 6-；X8 is Gln；X9 For Cys, Abu or Pen；X10 is 2-Nal, Phe analog, Tyr or Tyr analogs；X11 is 1-Nal, 2-Nal, Phe (3,4- Dimethoxy), Phe (3,4-Cl₂) or Trp；X12 be Acpc, Acbc, Acvc, Achc, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-MeLeu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, hLeu, Lys, Leu, Arg or THP；X13 For Cit, Asp, Dap, Dap (Peg2-Ac), Dap (burnt glutaric acid), Glu, hArg, Lys, Lys (Ac), Lys (benzoic acid), Lys (glutaric acid), Lys (IVA), Lys (the different Glu-Palm of Peg4-), Lys (burnt glutaric acid), Lys- (succinic acid), Asn, Orn, Gln, Arg or Val；X14 is Dab (Ac), Dap (Ac), His, Lys (Ac), Asn, Gln or Tyr；And X15 be Ala, β Ala, Gly, Asn, Gln or Ser.

In certain embodiments of Xa：X1 is not present；X2 is not present；X3 is not present；X4 is Cys, Abu or Pen；X5 is Dap, Dap (Ac), Gln, Ser, Thr or Asn；X6 is Thr；X7 is Trp；X8 is Gln；X9 is Cys, Abu or Pen；X10 is Phe analogs, Tyr or Tyr analogs；X11 is 2-Nal or Trp；X12 is Acpc, Acbc, Acvc, Achc, Aib, α-diethyl Base Gly, α-MeLys, α-MeLys (Ac), α-MeLeu, α-MeOrn, α-MeSer, α-MeVal, hLeu, Leu or THP；X13 is Cit, Asp, Glu, Lys, Lys (Ac), Asn or Gln；X14 is Dab (Ac), Asn or His；And X15 be Ala, β Ala, Gly, Asn or Gln.

In certain embodiments of Xa：X4 be Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Sec, 2- chloromethyl benzoic acid, mercaptopropionic acid, mercapto The chloro- acetic acid of base butyric acid, 2-, 3- chloropropionic acids, 4- chloro-butyric acids, 3- chlorine isobutyric acid, Abu, β-azido-Ala-OH, the sweet ammonia of propargyl Acid, 2- (3 '-cyclobutenyl) glycine, 2- allylglycines, 2- (3 '-cyclobutenyl) glycine, 2- (4 '-pentenyl) sweet ammonia Acid, 2- (5 '-hexenyl) glycine or Abu；X7 is Trp, Glu, Gly, Ile, Asn, Pro, Arg, Thr or OctGly or preceding State the corresponding Alpha-Methyl amino acid form of any one；X9 be Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Asp, Leu, Val, Phe or Ser, Sec, Abu, β-nitrine Base-Ala-OH, propargylglycine, 2-2- allylglycines, 2- (3 '-cyclobutenyl) glycine, 2- (4 '-pentenyl) sweet ammonia Acid, Ala, hCys, Abu, Met, MeCys, (D) Tyr or 2- (5 '-hexenyl) glycine；X10 is Tyr, Phe (4-OMe), 1- Nal, 2-Nal, Aic, α-MePhe, Bip, (D) Cys, Cha, DMT, (D) Tyr, Glu, His, hPhe (3,4- dimethoxy), hTyr、N-Me-Tyr、Trp、Phe(4-CONH₂), Phe (4- phenoxy groups), Thr, Tic, Tyr (3-tBu), Phe (4-tBu), Phe(4-CN)、Phe(4-Br)、Phe(4-NH₂), Phe (4-F), Phe (3,5-F₂)、Phe(4-CH₂CO₂H)、Phe(5-F)、 Phe (3,4-Cl₂)、Phe(4-CF₃)、Phe(4-OCH₃), Bip, Cha, 4- pyriylalanine, β hTyr, OctGly, Phe (4- N₃), Phe (4-Br), Phe [4- (2- amino ethoxies)] or Phe, Phe analog, Tyr analogs or any one of aforementioned right The Alpha-Methyl amino acid form answered；X11 is 2-Nal, 1-Nal, 2,4- dimethyl Phe, Bip, Phe (3,4-Cl₂), Phe (3,4- F₂)、Phe(4-CO₂H), β hPhe (4-F), α-Me-Trp, 4- phenylcyclohexyls, Phe (4-CF₃)、α-MePhe、βhNal、β HPhe, β hTyr, β hTrp, Nva (5- phenyl), Phe, His, hPhe, Tic, Tqa, Trp, Tyr, Phe (4-OMe), Phe (4- Me), Trp (2,5,7- tri--tertiary butyl), Phe (4-O allyls), Tyr (3-tBu), Phe (4-tBu), Phe (4- guanidine radicals, Phe (4-OBzl), Octgly, Glu (Bzl), 4- phenylbenzyls alanine, Phe [4- (2- amino ethoxies)], 5- hydroxyls-Trp, 6- Chloro- Trp, N-MeTrp, 1,2,3,4- tetrahydrochysenes-norharmane (norharman), Phe (4-CONH₂), Phe (3,4- dimethoxies Base), Phe (2,3-Cl₂), Phe (2,3-F₂), Phe (4-F), 4- phenylcyclohexyls alanine, Bip or any one of aforementioned corresponding Alpha-Methyl amino acid form；X12 be His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, Tertiary butyl-Ala, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acvc, Acbc, Agp, Aib, α-diethyl Gly, α - MeLys、α-MeLys(Ac)、α-Me-Leu、α-MeOrn、α-MeSer、α-MeVal、Aib、D-Ala、(D)Asn、(D)Asp、 (D)Leu、(D)Phe、(D)Tyr、Aib、α-MeLeu、α-MeOrn、β-Aib、β-Ala、βhAla、βhArg、βhLeu、βhVal、 β-spiral shell-pip, Glu, hArg, Ile, Lys, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Ser, Thr, Tle, tertiary butyl- The corresponding Alpha-Methyl amino acid forms of any one of Gly or aforementioned；X13 be Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Arg, Orn、Val、βhAla、Lys(Ac)、(D)Asn、(D)Leu、(D)Phe、(D)Thr、Ala、α-MeLeu、Aib、β-Ala、β- Glu, β hLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, hLeu, Asn, Ogl, Pro, Any one of Gln, Ser, β-spiral shell-pip, Thr, Tba, Tle or Aib, Cit, hArg, Lys, Asn, Orn, Gln or aforementioned are corresponding Alpha-Methyl amino acid form；X14 be Phe, Tyr, Glu, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr、TicβhPhe、Arg、Lys(Ac)、His；The corresponding Alpha-Methyl amino of any one of Dap (Ac), Dab (Ac), Asp or aforementioned Sour form；X15 be Gly, Ser, Thr, Gln, Ala, (D) Ala, (D) Asn, (D) Asp, (D) Leu, (D) Phe, (D) Thr, The corresponding Alpha-Methyl ammonia of any one of Aea, Asp, Asn, Glu, Phe, Gly, Lys, Leu, Pro, Arg, β-Ala, Sarc or aforementioned Base acid form；X16 is Asp, Glu, Ala, AEA, AEP, β hAla, Gaba, Gly, Ser, Pro, Asn, Thr or is not present, or For any one of aforementioned corresponding Alpha-Methyl amino acid form；And X17 is Leu, Lys, Arg, Glu, Ser, Gly, Gln or does not deposit , or be any one of aforementioned corresponding Alpha-Methyl amino acid form.

In certain embodiments of the inhibitor peptides of Xa, key is disulfide bond, thioether bond, lactam bond, triazole ring, selenide Key, two selenium keys or alkene key.

In the specific embodiment of the inhibitor peptides of Xa, X4 Cys and X9 are Cys, and the key is two sulphur Key.In a particular embodiment, X4 Pen and X9 are Pen, and the key is disulfide bond.In certain embodiments： X7 is Trp；X10 is Phe, Tyr, Phe analog or Tyr analogs；X11 is Trp, 1-Nal or 2-Nal；And X12 be Aib, α-Me-Lys, α-Me-Leu, Achc, Acvc, Acpc, Acbc or THP.In certain embodiments：X7 is Trp；X10 be Phe, Tyr, Phe analog or Tyr analogs；X11 is Trp, 1-Nal or 2-Nal；And X12 is Aib, α-Me-Lys or α-Me- Leu.In a particular embodiment, inhibitor peptides include any one of following amino acid sequences：Pen-Q-T-W-Q-Pen- [Phe(4-OMe)]-[2-Nal]-[α-Me-Lys]-E-N-G；Pen-N-T-W-Q- [Pen]-[Phe [4- (2- amino ethoxies Base)]-[2-Nal]-[Aib]-[Lys (Ac)]-N-N；Pen-Q-T-W-Q- [Pen]-[Phe [4- (2- amino ethoxies)]-[2- Nal]-[α-MeLeu]-[Lys(Ac)]-N-N；Or Pen-Q-T-W-Q- [Pen]-[Phe (4-CONH₂)]-[2-Nal]-[α- MeLys]-[Lys (Ac)]-N-N, wherein disulfide bond of the inhibitor peptides between two Pen amino acid.

In the specific embodiment of the inhibitor peptides of Xa, X4 is with the carbon side chain that can be combined with X9 formation thioethers Amino acid, aliphatic acid, alicyclic acid or the 2- of modification methyl aromatic acids；X9 is the sulfur-containing amino acid that thioether bond can be formed with X4, And the key between X4 and X9 is thioether bond.In certain embodiments, X4 Abu, 2- chloromethyl benzoic acids, mercaptopropionic acid, The chloro- acetic acid of mercaptobutyric acid, 2-, the chloro- propionic acid of 3-, the chloro- butyric acid of 4-, the chloro- isobutyric acids of 3-；And X9 be Abu, Cys, Pen, hCys, D-Pen, D-Cys or D-hCys.In certain embodiments, X4 Abu；And X9 is Cys.In certain embodiments, X7 For Trp；X10 is Phe, Tyr, Phe analog or Tyr analogs；X11 is Trp, 1-Nal or 2-Nal；And X12 is α-Me- Lys, α-Me-Leu, α-Me-Ser, α-Me-Val, Achc, Acvc, Acpc, Acbc or [4- amino -4- carboxyls-oxinane]. In certain embodiments, X7 Trp；X10 is Phe, Tyr, Phe analog or Tyr analogs；X11 is Trp, 1-Nal or 2- Nal；And X12 is α-Me-Lys or [4- amino -4- carboxyls-oxinane].In a particular embodiment, inhibitor peptides include Any one of following amino acid sequences：[Abu]-Q-T-W-Q-C-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]-E-N- G；[Abu]-Q-T-W-Q-C- [Phe (4- (2- amino ethoxies))]-W- [α-MeLys]-E-N-G；Or [Abu]-Q-T-W-Q- C- [Phe [4- (2- amino ethoxies)]]-[2-Nal]-[4- amino -4- carboxyls-oxinane]-E-N-N, wherein inhibitor peptides Thioether bond between Abu and C.

In certain embodiments of the inhibitor peptides of Xa：X4 is Pen, Cys or hCys；X5 is arbitrary amino acid；X6 is Arbitrary amino acid；X7 is Trp, Bip, Gln, His, Glu (Bzl), 4- phenylbenzyls alanine, Tic, Phe [4- (2- amino second Oxygroup)], Phe (3,4-Cl₂), Phe (4-OMe), 5- hydroxyls-Trp, chloro- Trp, N-MeTrp, α-Me-Trp of 6-, 1,2,3,4- Tetrahydrochysene-norharmane, Phe (4-CO₂H)、Phe(4-CONH₂), Phe (3,4- dimethoxy), Phe (4-CF₃)、Phe(4- TBu), the corresponding Alpha-Methyl of any one of β β-two PheAla, Glu, Gly, Ile, Asn, Pro, Arg, Thr or Octgly or aforementioned Amino acid form；X8 is arbitrary amino acid；X9 is Pen, Cys or hCys；X10 be 1-Nal, 2-Nal, Aic, Bip, (D) Cys, Cha, DMT, (D) Tyr, Glu, Phe, His, Trp, Thr, Tic, Tyr, 4- pyridyl group Ala, Octgly, Phe analogs or Tyr Analog (optionally, (3,4-F Phe₂), Phe (3,4-Cl₂), F (3-Me), Phe [4- (2- amino ethoxies)], Phe [4- (2- (acetyl-amino ethoxy)], Phe (4-Br), Phe (4-CONH₂), Phe (4-Cl), Phe (4-CN), Phe (4- guanidine radicals), Phe (4-Me)、Phe(4-NH₂)、Phe(4-N₃), Phe (4-OMe) or Phe (4-OBzl)) or any one of aforementioned corresponding Alpha-Methyl ammonia Base acid form；X11 is 2-Nal, 1-Nal, 2,4- dimethyl Phe, Bip, Phe (3,4-Cl₂), Phe (3,4-F₂)、Phe(4- CO₂H), β hPhe (4-F), α-Me-Trp, 4- phenylcyclohexyls, Phe (4-CF₃)、α-MePhe、βhNal、βhPhe、βhTyr、β HTrp, Nva (5- phenyl), Phe, His, hPhe, Tic, Tqa, Trp, Tyr, Phe (4-OMe), Phe (4-Me), Trp (2,5,7- Three-tertiary butyls), Phe (4-O allyls), Tyr (3-tBu), Phe (4-tBu), Phe (4- guanidine radicals, Phe (4-OBzl), Octgly, Glu (Bzl), 4- phenylbenzyls alanine, Phe [4- (2- amino ethoxies)], 5- hydroxyls-Trp, 6- chloro- Trp, N- MeTrp, 1,2,3,4- tetrahydrochysenes-norharmane, Phe (4-CONH₂), Phe (3,4-OMe₂) Phe (2,3-Cl₂), Phe (2,3- F₂), Phe (4-F), 4- phenylcyclohexyls alanine or Bip or any one of aforementioned corresponding Alpha-Methyl amino acid form；X12 For α-MeLys, α-MeOrn, α-MeLeu, α-MeVal, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, MeLeu、Aib、(D)Ala、(D)Asn、(D)Leu、(D)Asp、(D)Phe、(D)Thr、3-Pal、Aib、β-Ala、βhGlu、β HAla, β hLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, hArg, HLeu, Ile, Lys, Leu, Asn, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr or Tle are aforementioned The corresponding Alpha-Methyl amino acid form of any one；X13 be Lys (Ac), (D) Asn, (D) Leu, (D) Thr, (D) Phe, Ala, Aib, α-MeLeu, β-Ala, β hGlu, β hAla, β hLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Lys, Arg, Orn, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, Lys, Leu, Asn, Ogl, Pro, Gln, Asp, Arg, Ser, spiral shell-pip, Thr, Tba, Tlc, Val or Tyr or the corresponding Alpha-Methyl amino acid form of aforementioned any one；X14 be Asn, Glu, Phe, Any one of Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr, Lys (Ac), Orn or aforementioned Corresponding Alpha-Methyl amino acid form；X15 is Gly, (D) Ala, (D) Asn, (D) Asp, Asn, (D) Leu, (D) Phe, (D) Any one of Thr, Ala, AEA, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg or Ser, β-Ala, Arg or aforementioned are right The Alpha-Methyl amino acid form answered；X16 is not present, is that Gly, Ala, Asp, Ser, Pro, Asn or Thr or aforementioned any one are right The Alpha-Methyl amino acid form answered；X17 is not present, is Glu, Ser, Gly or Gln or the corresponding Alpha-Methyl ammonia of aforementioned any one Base acid form；X18 is not present or is arbitrary amino acid；X19 is not present or is arbitrary amino acid；And X20 be not present or Person is arbitrary amino acid.In a particular embodiment, the key between X4 and X9 is disulfide bond.In certain embodiments, X1, X2 It is not present with X3.In certain embodiments, X17, X19 and X20 are not present.In certain embodiments, one of X4 or X9 or Both for Pen.In certain embodiments, X4 and X9 is Pen.In a particular embodiment, X18 is (D)-Lys.At certain In a little embodiments, inhibitor peptides include it is one or more of following, two or more, three or more or four It is a：X5 is Arg, Asn, Gln, Dap, Orn；X6 is Thr or Ser；X7 be Trp, 2-Nal, 1-Nal, Phe (4-O allyls), Tyr (3-tBu), Phe (4-tBu), Phe (4- guanidine radicals), Phe (Bzl) or Phe (4-Me), 5- hydroxyls-Trp, 6- chloro- Trp, N- MeTrp, α-MeTrp or 1,2,3,4- tetrahydrochysenes-norharmane；And X8 is Gln, Val, Phe, Glu, Lys.In certain implementations In scheme, inhibitor peptides include it is one or more of following, two or more, three or more, four or more, Five or more, six or more or seven：X10 is Tyr, Phe (4-OBzl), Phe (4-OMe), Phe (4- CONH₂), Phe (3,4-Cl₂)、Phe(4-tBu)、Phe(4-NH₂)、Phe(4-Br)、Phe(4-CN)、Phe(4-CO₂H)、Phe (4- (2 amino ethoxy)) or Phe (4- guanidine radicals)；X11 is Trp, 2-Nal, 1-Nal, Phe (4-O allyls), Tyr (3- TBu), Phe (4-tBu), Phe (4- guanidine radicals), Phe (Bzl) or Phe (4-Me), 5- hydroxyls-Trp, the chloro- Trp, N-MeTrp of 6-, α-MeTrp or 1,2,3,4- tetrahydrochysenes-norharmane；X12 is Arg, α-MeLys, α-MeLeu, Aib or α-MeOrn；X13 is Lys, Glu or Lys (Ac)；X14 is Phe or Asn；X15 is Gly, Sr or Ala；And X16 be not present or be AEA.In certain realities It applies in scheme, X4 and X9 are Pen；X5 is Gln；X6 is Thr；X7 is Trp；X8 is Gln；X10 is Tyr, Phe (4-OMe) or 2- Nal；X11 is Trp, 2-Nal or 1-Nal；X12 is Arg, α MeLys or α-MeOrn；X13 is Lys, Glu or Lys (Ac)；X14 For Phe or Asn；X15 is Gly；And X16 is not present.In certain embodiments, one or more of X1, X2 and X3 be not no In the presence of；And one or more of X17, X18, X19 and X20, two or more, three or more or four do not deposit .

In certain embodiments of the inhibitor peptides of Xa：X4 is Abu, Pen or Cys；X7 be Trp, Bip, Gln, His, Glu (Bzl), 4- phenylbenzyls alanine, Tic, Phe [4- (2- amino ethoxies)], Phe (3,4-Cl₂)、Phe(4-OMe)、 Chloro- Trp, N-MeTrp, α-MeTrp of 5- hydroxyls-Trp, 6-, 1,2,3,4- tetrahydrochysenes-norharmane, Phe (4-CO₂H)、Phe (4-CONH₂), Phe (3,4- dimethoxy), Phe (4-CF₃), β β-two PheAla, Phe (4-tBu), Glu, Gly, Ile, Asn, The corresponding Alpha-Methyl amino acid form of any one of Pro, Arg, Thr or Octgly or aforementioned；X9 is Abu, Pen or Cys；X10 is 1-Nal, 2-Nal, Aic, Bip, (D) Cys, Cha, DMT, (D) Tyr, Glu, Phe, His, Trp, Thr, Tic, Tyr, 4- pyridine Base Ala, Octgly, Phe analog or Tyr analogs or the corresponding Alpha-Methyl amino acid form of aforementioned any one；X11 is 2- Nal, 1-Nal, 2,4- dimethyl Phe, Bip, 4- phenylcyclohexyl, Glu (Bzl), 4- phenylbenzyls alanine, Tic, Phe [4- (2- amino ethoxies)], Phe (3,4-Cl₂), Phe (3,4-F₂), β hPhe (4-F), Phe (4-OMe), 5- hydroxyls-Trp, 6- Chloro- Trp, N-MeTrp, α-MeTrp, 1,2,3,4- tetrahydrochysenes-norharmane, Phe (4-CO₂H)、Phe(4-CONH₂), Phe (3, 4- dimethoxys), Phe (4-CF₃), Phe (2,3-Cl₂), Phe (2,3-F₂), Phe (4-F), 4- phenylcyclohexyls alanine, α- MePhe, β hNal, β hPhe, β hTyr, β hTrp, Bip, Nva (5- phenyl), Phe, His, hPhe, Tqa, Trp, Tyr, Phe (4- Me), Trp (2,5,7- tri--tertiary butyl), Phe (4-O allyls), Tyr (3-tBu), Phe (4-tBu), Phe (4- guanidine radicals), Phe (4-OBzl) or Octgly or the corresponding Alpha-Methyl amino acid form of aforementioned any one；X12 is α-MeLys, α-MeOrn, α- MeLeu、MeLeu、Aib、(D)Ala、(D)Asn、(D)Leu、(D)Asp、(D)Phe、(D)Thr、3-Pal、Aib、β-Ala、β HGlu, β hAla, β hLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, HArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr or Tle or The corresponding Alpha-Methyl amino acid form of the aforementioned any one of person；X13 be Lys (Ac), (D) Asn, (D) Leu, (D) Thr, (D) Phe, Ala, Aib, α-MeLeu, β Ala, β hGlu, β hAla, β hLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Arg, Orn, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, Lys, Leu, Asn, Ogl, Pro, Gln, Asp, Arg, Ser, spiral shell-pip, Thr, Tba, Tlc, Val or Tyr or the corresponding Alpha-Methyl amino acid form of aforementioned any one；X14 be Asn, Glu, Phe, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr or the corresponding α-first of aforementioned any one Base amino acid form；X15 be Gly, (D) Ala, (D) Asn, (D) Asp, Asn, (D) Leu, (D) Phe, (D) Thr, Ala, AEA, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg or Ser or the corresponding Alpha-Methyl amino acid form of aforementioned any one, Or X15 be Gly, (D) Ala, (D) Asn, (D) Asp, Asn, (D) Leu, (D) Phe, (D) Thr, Ala, Asn, Ser, AEA, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg or Ser or the corresponding Alpha-Methyl amino acid form of aforementioned any one； X16 is not present, is Gly, Ala, Asp, Ser, Pro, Asn or Thr or the corresponding Alpha-Methyl amino acid form of aforementioned any one； And X17 is not present, is Glu, Ser, Gly or Gln or the corresponding Alpha-Methyl amino acid form of aforementioned any one.Specific real It applies in scheme, inhibitor peptides are cyclized via the intramolecular bond between X4 and X9.In certain embodiments, in X1, X2 and X3 One or more is not present.In certain embodiments, one or more of X17, X19 and X20 are not present.In certain implementations In scheme, it is not Abu that one of X4 or X9, which are another in Abu and X4 or X9,.In certain embodiments, inhibitor peptides Including it is one or more of following, two or more, three or more or four：X5 be Arg, Gln, Dap or Orn；X6 is Thr or Ser；X7 is Trp, 2-Nal, 1-Nal, Phe (4-O allyls), Tyr (3-tBu), Phe (4-tBu), Phe (4- guanidine radicals), Phe (4-OBzl), Phe (4-Me), 5- hydroxyls-Trp, chloro- Trp, N-MeTrp or α-MeTrp of 6-, 1,2,3,4- Tetrahydrochysene-norharmane；And X8 is Gln, Val, Phe, Glu or Lys.In certain embodiments, under inhibitor peptides include One or more of state, two or more, three or more, four or more, five or more, six or more It is multiple or seven：X10 is Tyr, Phe (4-OBzl), Phe (4-OMe), Phe (4-CONH₂), Phe (3,4-Cl₂)、Phe(4- tBu)、Phe(4-NH₂)、Phe(4-Br)、Phe(4-CN)、Phe(4-CO₂H), Phe (4- (2 amino ethoxy)) or Phe (4- guanidines Base)；X11 is Trp, 2-Nal, 1-Nal, Phe (4-O allyls), Tyr (3-tBu), Phe (4-tBu), Phe (4- guanidine radicals), Phe (Bzl) or Phe (4-Me), 5- hydroxyls-Trp, 6- chloro- Trp, N-MeTrp, α-MeTrp or 1,2,3,4- tetrahydrochysenes-remove Jia Haer It is full；X12 is Arg, hLeu, (D) Asn, Aib, α-MeLys, α-MeLeu or α-MeOrn；X13 is Lys, Glu or Lys (Ac)； X14 is Phe or Asn；X15 is Gly, Ser or Ala or X15 is Asn, Gly, Ser, β Ala or Ala；And X16 is not present Or it is AEA.

In any specific embodiment of inhibitor peptides, X4 and X9 are Pen.In a particular embodiment, X4 and X9 forms disulfide bond.

In a particular embodiment, X4 is Abu and X9 is Cys.In a particular embodiment, X4 and X9 forms thioether Key.

In a particular embodiment, inhibitor peptides include SEQ ID NO：The amino of any of 365-370,857-1029 Acid sequence.In a particular embodiment, inhibitor peptides are cyclized via the key between X4 and X9, and inhibitor peptides inhibit white thin The combination of born of the same parents' interleukin -23 (IL-23) and IL-23 receptor.

In certain embodiments of the inhibitor peptides of Xa, the inhibitor peptides include formula (V), (Va), (Vb), (Vc), (Vd), amino acid sequence shown in any of (Ve), (Vf), (Vg) and (Vh).

In certain embodiments of the inhibitor peptides of Xa, the inhibitor peptides include any in following amino acid sequences It is a：

[Palm]-[different Glu]-[PEG4]-[Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2- Nal]-[Aib]-[Lys(Ac)]-NNNH₂；

[[2-Nal]-[Aib]-[(PEG4- is different by Lys by Phe [4- (2- amino ethoxies)]-by Ac- [Pen]-NTWQ- [Pen]- Glu-Palm)]-NN-NH₂；

Ac-[Pen]-QTWQ-[Pen]-Phe(4-CONH₂)-[2-Nal]-[α-MeLys(Ac)]-[Lys(Ac)]-NN- NH₂；

[octyl]-[different Glu]-[PEG4]-[Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2- Nal]-[Aib]-[Lys(Ac)]-NN-NH₂；

[octyl]-[PEG4]-[Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]- [Lys(Ac)]-NN-NH₂；

[Palm]-[PEG4]-[Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]- [Lys(Ac)]-NN-NH₂；

[[2-Nal]-[Aib]-[(PEG4- is pungent by Lys by Phe [4- (2- amino ethoxies)]-by Ac- [Pen]-NTWQ- [Pen]- Base)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (PEG4- Palm)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)-(PEG4-Palm)]-[2-Nal]-[Aib]- [Lys(Ac)]NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)-(PEG4- lauryls)]-[2-Nal]- [Aib]-[Lys(Ac)]-NN-NH₂；

Ac-[Pen]-QTWQ-[Pen]-Phe(4-CONH₂)-[2-Nal]-[α-MeLys(PEG4-Palm)-[Lys (Ac)]-NN-NH₂；

Ac-[Pen]-QTWQ-[Pen]-Phe(4-CONH₂)-[2-Nal]-[α-MeLys (PEG4- lauryls)]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)-(the different Glu-Palm of PEG4-)]-[2-Nal]- [Aib]-[Lys(Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)-(the different Glu- lauryls of PEG4-)]-[2- Nal]-[Aib]-[Lys(Ac)]-NN-NH₂；

Ac-[Pen]-QTWQ-[Pen]-Phe(4-CONH₂)-[2-Nal]-[α-MeLys (the different Glu-Palm of PEG4-)]- [Lys(Ac)]-NN-NH₂；

Ac-[Pen]-QTWQ-[Pen]-Phe(4-CONH₂)-[2-Nal]-[α-MeLys (the different Glu- bays of PEG4- Base)]-[Lys (Ac)]-NN-NH₂；

Ac-[Pen]-QTWQ-[Pen]-Phe(4-CONH₂)-[2-Nal]-[α-MeLys(IVA)]-[Lys(Ac)]-NN- NH₂；

Ac-[Pen]-QTWQ-[Pen]-Phe(4-CONH₂)-[2-Nal]-[α-MeLys (biotin)]-[Lys (Ac)]- NN-NH₂；

Ac-[Pen]-QTWQ-[Pen]-Phe(4-CONH₂)-[2-Nal]-[α-MeLys (octyl)]-[Lys (Ac)]- NN-NH₂；

Ac- [Pen]-[Lys (IVA)]-TWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]- [Lys(Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- [Lys(IVA)]-N-NH₂；

Ac- [Pen]-[Lys (biotin)]-TWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]- [Aib]-[Lys(Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- [Lys (biotin)]-N-NH₂；

Ac- [Pen]-[Lys (octyl)]-TWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]- [Lys(Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- [Lys (octyl)]-N-NH₂；

Ac- [Pen]-[Lys (Palm)]-TWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal] -- [Aib]- [Lys(Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- Lys(Palm)]-N-NH₂；

Ac- [Pen]-[Lys (PEG8)]-TWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]- [Lys(Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- [Lys(PEG8)]-N-NH₂；

Ac- [Pen]-K (Peg11-Palm) TWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]- [Lys(Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal] -- [Aib]-[Lys (Ac)]- [Lys(Peg11-palm)]-N-NH₂；

Ac- [Pen]-[Cit]-TW- [Cit]-[Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal] -- [Aib]- [Lys(Ac)]-NN-NH₂；

Ac- [Pen]-[Lys (Ac)]-TW- [Cit]-[Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]- [Aib]-[Lys(Ac)]-NN-NH₂；

Ac- [Pen]-NT- [Phe (3,4-OCH3) 2]-Q- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]- [Aib]-[Lys(Ac)]-NN-NH₂；

Ac- [Pen]-NT- [Phe (2,4-CH3) 2]-Q- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]- [Aib]-[Lys(Ac)]-NN-NH₂；

Ac- [Pen]-NT- [Phe (3-CH3)]-Q- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]- [Aib]-[Lys(Ac)]-NN-NH₂；

Ac- [Pen]-NT- [Phe (4-CH3)]-Q- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]- [Aib]-[Lys(Ac)]-NN-NH₂；

Ac [(D) Arg]-[Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-N-[βAla]-NH₂；

Ac- [(D) Tyr]-[Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]- [Lys(Ac)]-N-[βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- QN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- [Lys(Ac)]-N-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-N- [Lys(Ac)]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- QQ-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-Q- [βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-N- [Cit]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- [Cit]-NNH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- [Cit]-Q-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- [Cit]-[Lys(Ac)]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- [Lys(Ac)]-[Cit]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-QN- [β Ala]- NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-E- [Cit]-Q- NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Cit]-N- [Cit]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Cit]-Q- [Cit]-NH₂；

Ac- [Pen]-[Cit]-TWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-QNN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-ENQ-NH₂；

Ac- [Pen]-GPWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- NN-NH₂；

Ac- [Pen]-PGWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- NN-NH₂；

Ac- [Pen]-NTWN- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- NN-NH₂；

Ac- [Pen]-NSWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- NN-NH₂；

Ac- [Pen]-N- [Aib]-WQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NTW- [Aib]-[Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]N-[Aib]-NH₂；

Ac- [Pen]-QTW- [Lys (Ac)]-[Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]- [Lys(Ac)]-NN-NH₂；

Ac- [Pen]-[Lys (Ac)]-TWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal] -- [Aib]- [Lys(Ac)]NNNH₂；

Ac- [Pen]-QVWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- NN-NH₂；

Ac- [Pen]-NT- [2-Nal]-Q- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NT- [1-Nal]-Q- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[α-MeLeu]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[α-MeLys]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- carboxyls-four Hydrogen pyrans]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[α-MeLeu]-[Lys (Ac)]-N-[βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[α-MeLys]-[Lys (Ac)]-N-[βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- carboxyls-four Hydrogen pyrans]-[Lys (Ac)]-N- [β Ala]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- LN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- GN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- SN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- [Aib]-N-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- FN-NH₂；

Ac- [Pen]-NTW- [Cit]-[Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- [Tic]-[βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- [nLeu]-[βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-G- [βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-R- [βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal] -- [Aib]-[Lys (Ac)]- W-[βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal] -- [Aib]-[Lys (Ac)]- S-[βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal] -- [Aib]-[Lys (Ac)]- L-[βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal] -- [Aib]-[Lys (Ac)]- [AIB]-[βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal] -- [Aib]-[Lys (Ac)]- [N-MeAla]-[βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- [2-Nap]-[βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-F- [βAla]-NH₂；

Ac- [(D) Arg]-[Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino- 4- carboxyls-oxinane]-[Lys (Ac)] NNNH₂；

Biotin-[PEG4]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino- 4- carboxyls-oxinane]-ENN-NH₂；

Ac- rings [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- carboxyls-tetrahydrochysene Pyrans]-[Lys (Ac)]-NN-NH₂；

Ac- [(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- Carboxyl-oxinane]-[Lys (Ac)]-NN-NH₂；

Ac-E- [(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino- 4- carboxyls-oxinane]-ENN-NH₂；

Ac- [(D) Asp]-[(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]- [4- amino -4- carboxyls-oxinane]-ENN-NH₂；

Ac-R- [(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino- 4- carboxyls-oxinane]-ENN-NH₂；

Inoethoxy)]-[2-Nal]-[4- amino -4- carboxyls-oxinane]-ENN-NH₂；

Ac-F- [(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino- 4- carboxyls-oxinane]-ENN-NH₂；

Ac- [(D) Phe]-[(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]- [4- amino -4- carboxyls-oxinane]-ENN-NH₂；

Ac- [2-Nal]-[(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]- [4- amino -4- carboxyls-oxinane]-ENN-NH₂；

Ac-T- [(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino- 4- carboxyls-oxinane]-ENN-NH₂；

Ac-L- [(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino- 4- carboxyls-oxinane]-ENN-NH₂；

Ac- [(D) Gln]-[(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]- [4- amino -4- carboxyls-oxinane]-ENN-NH₂；

Ac- [(D) Asn]-[(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]- [4- amino -4- carboxyls-oxinane]-ENN-NH₂；

Ac- rings [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)-(PEG4-Alexa488)]-[2-Nal]-[4- Amino -4- carboxyls-oxinane]-ENN-NH₂；

[Alexa488]-[PEG4]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)] -- [2-Nal]-[4- Amino -4- carboxyls-oxinane]-ENN-NH₂；

[Alexa647]-[PEG4]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- Amino -4- carboxyls-oxinane]-ENN-NH₂；

[Alexa-647]-[PEG4]-[(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]- [2-Nal]-[4- amino -4- carboxyls-oxinane]-[Lys (Ac)]-NN-NH₂；

[Alexa647]-[PEG12]-[(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]- [2-Nal]-[4- amino -4- carboxyls-oxinane]-[Lys (Ac)]-NN-NH₂；And

[Alexa488]-[PEG4]-[(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2- Nal]-[4- amino -4- carboxyls-oxinane]-[Lys (Ac)]-NN-NH₂,

The wherein described inhibitor peptides via between 2 Pen residues disulfide bond or pass through the sulphur between Abu and Cys residues Ehter bond is cyclized, and the wherein described inhibitor peptides inhibit the combination of Interleukin-23 (IL-23) and IL-23 receptor.

In a particular embodiment, any inhibitor peptides as described herein include the one or more for being conjugated to inhibitor peptides Half-life extension moiety and/or one or more junction portions.In a particular embodiment, half-life extension moiety is via one Or multiple junction portions are conjugated with inhibitor peptides.

In certain embodiments, any inhibitor peptides as described herein also include conjugated chemical substituents.Specific In embodiment, conjugated chemical substituents are lipophilic substituent or polymer moieties, for example, Ac, Palm, γ Glu-Palm, The different Glu-Palm of different Glu-Palm, PEG2-Ac, PEG4-, (PEG)₅- Palm, succinic acid, glutaric acid, pyroglutamic acid, benzoic acid, IVA, octanoic acid, 1,4-Diaminobutane, isobutyl group or biotin.In certain embodiments, conjugated chemical substituents are point The polyethylene glycol that son amount is 400Da to 40,000Da.

On the other hand, the present invention includes the inhibitor peptides comprising Formulas I structure or its pharmaceutically acceptable salt or solvent Compound：

R¹-X-R²(I)

Wherein

R¹For key, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, C1-C20 hydrocarbon acyl groups, and Including any one of aforementioned individual PEGylated forms or as the PEGylated forms of introns；

R²For key, OH or NH₂；And

X be arbitrary peptide sequence described herein, for example, Xa, I, Ia-It, II, IIa-IId, III, IIIa-IIIe, IV, IVa-IVb, V or Va-Vh.

In related aspect, the present invention includes the peptide dimer inhibitor of Interleukin-23 receptor, wherein the peptide two Aggressiveness inhibitor includes the two peptide monomer subunits connected via one or more junction portions, wherein each peptide monomer subunit has There are sequence or structure shown in this article.In certain embodiments, one or two peptide monomer subunit is via between X4 and X9 Intramolecular bond is cyclized.In certain embodiments, one or two intramolecular bond is disulfide bond, thioether bond, lactam bond, selenide Key, two selenium keys or alkene key.In certain embodiments, connector is shown in table 2 or arbitrary connector as described herein.In certain realities It applies in scheme, junction portion is diethylene glycol connector, iminodiacetic acid (IDA) connector, β-Ala- iminodiacetic acids (β- Ala-IDA) connector or PEG connectors.In a particular embodiment, the ends N- of each peptide monomer subunit are connected by junction portion. In a particular embodiment, the ends C- of each peptide monomer subunit are connected by junction portion.In certain embodiments, connector will The ends N-, the ends C- or internal amino acid of internal amino acid residue and other peptide monomer subunits at least one peptide monomer subunit are residual Base connects.

In other related aspects, the present invention includes the inhibitor peptides containing the coding present invention or the peptide dimerization of the present invention The polynucleotides of the sequence of one or two peptide monomer subunit of body inhibitor.The invention also includes contain the polynucleotides Carrier.

On the other hand, the present invention includes inhibitor peptides or peptide dimer inhibitor and pharmaceutically acceptable containing the present invention Carrier, excipient or diluent pharmaceutical composition.In a particular embodiment, pharmaceutical composition includes enteric coating. In certain embodiments, enteric coating protection described pharmaceutical composition is simultaneously released in the lower gastrointestinal tract system of object.

On the other hand, the present invention includes the side with the relevant disease of IL-23 signal transductions treated or prevented in object Method comprising provide the inhibitor peptides or pharmaceutical composition of a effective amount of present invention to the object, the disease includes but not It is limited to inflammatory bowel disease (IBD), ulcerative colitis, Crohn disease, chylous diarrhea (nontropical sprue) and serum reverse Answer the relevant enteropathy of negative arthropathies, microscopic colitis, collagenous colitis, eosinophilic gastroenteritis, with radiotherapy or The relevant colitis of chemotherapy and the relevant colitis of congenital immunity illness (such as 1 type of leukocyte adhesion deficiency disease), chronic granuloma Disease, glycogen storage disease 1b types, Hermansky-Pudlak syndromes, Chediak-Higashi syndromes and Wiskott- Caused haustrum inflammation, human primary gastrointestinal cancers, pancreatitis, pancreas after Aldrich syndromes, proctocolectomy and ileoanal anastomosis Island element dependent diabetes, mastitis, cholecystitis, cholangitis, pericholangitis, chronic bronchitis, chronic sinusitis, asthma, silver Bits disease or graft versus host disease(GVH disease).In certain embodiments, the inflammatory bowel disease is ulcerative colitis or Crohn disease. In a particular embodiment, the inhibitor peptides or peptide dimer inhibitor inhibit Interleukin-23 (IL-23) and leucocyte The combination of -23 receptor of interleukin (IL-23R).In certain embodiments, pass through oral administration path, intravenous administration route, abdomen Film administration method, intradermal administration approach, subcutaneous administration approach, intramuscular administration method, intrathecal administration method, sucking application way Diameter, vaporization administration method, atomization administration method, sublingual administration route, oral administration approach, parenteral administration approach, rectum are applied With approach, intraocular administration method, sucking administration method, vaginal application approach or topical routes of administration pharmaceutical composition is provided to object Object.In a particular embodiment, pharmaceutical composition is provided by oral administration, for treating inflammatory bowel disease (IBD), ulcerative colitis Scorching, Crohn disease.In certain embodiments, to the object in part, parenteral, intravenous, subcutaneous, peritonaeum or vein Pharmaceutical composition is provided, for treating psoriasis.

Brief description

It is bent that Fig. 1 provides the rat IL-23 dose responses as measured by the level of IL-17A in being analyzed as rat spleen cells The example of line.

Fig. 2 is to show that the IL-12 of the IFN γ of the human PBMC come the compound A for specified amount of using by oneself or compound B processing is relied on Property generate figure.

Fig. 3 shows the result from the 7th day DAI value.It is measured and is counted using Student t-test (GraphPad Prism) Significance analysis.Difference is registered as significantly, * p ＜ 0.05, * * p ＜ 0.01, * * * p ＜ 0.001, * * * * p ＜ 0.0001。

Fig. 4 shows people IL23R, hyperkine R, rat IL23R, chimpanzee IL-23R, dog IL-23R and ox IL-23R's The comparison of amino acid sequence, highly conserved amino acid residue add shade.Show do not have in other species IL-23R shown in Hyperkine R region, and can by the present invention certain inhibitor peptides combine the regions IL23R indicate by a dotted line.

Fig. 5 is the table for the research and design for summarizing the rat colonitis for TNBS inductions.

Fig. 6 A-6D are the figure (Fig. 6 A) for showing colon weight/length, the figure (table 6B) of colon wall thickness, and colon macroscopic view is commented Point figure (table 6C) or in sham-operation processing, medium processing or the anti-IL23p19 antibody with specified amount or compound C processing Afterwards, pass through the figure of myeloperoxidase (MPO) abundance in proximal colonic extract quantitative ELISA.Value is shown as average Value ± SD.Significance,statistical is assessed by single factor test ANOVA：* 0.05 ＜；* ＜ 0.01；* * p ＜ 0.001；* * * p ＜ 0.0001；Ns, not significantly.

Fig. 7 is provided is present in the colon damage in animal after sham-operation handles (the picture left above), medium processing (top right plot) The micrograph (display transmural inflammation, there are slough and the not crypts of mucous membrane) of wound, anti-IL23p19 antibody processing is (left Figure below) or 160mg/kg/d compound C processing (bottom-right graph) after be present in the micrograph of Traumatic Colon in animal (display be limited to The damage of mucous membrane).

Fig. 8 A-8E are to show in medium processing, handled with anti-IL23p19 antibody or with the compound C processing of specified amount The figure (Fig. 8 A) of inflammation afterwards, the figure (Fig. 8 B) of mucosal necrosis, the figure (Fig. 8 C) of body of gland loss, the figure (Fig. 8 D) of colon wall thickness With the figure (Fig. 8 E) of histological score.

Fig. 9 shows the concentration (left figure) of the compound C in the blood plasma and proximal colonic that last PO dosage latter hour measures, And as what is measured by rat spleen cells analysis (middle graph) and rat IL23RELISA analyses (right figure) is more than its activity IC75 multiple.

Figure 10 provides the structure for describing certain inhibitor peptides and illustrates the signal of the representative types of the key between X4 and X9 Figure.

Figure 11 A-11E show (the SEQ ID NO of IL-23R inhibitor peptides peptide 993：993) pharmacokinetic data.Figure 11A show after peptide 993 is administered orally until in the blood plasma measured at 24 hours different time points peptide 993 concentration (nM).Figure 11 B-11D, which are shown, is derived from peyer's patches (Peyer ' s Patch) (Figure 11 B), small intestine (Figure 11 C) and colon (figure The concentration (nM) of peptide 993 in sample 11D).Dotted line indicates 350mM.Figure 11 E are shown after oral administration in 24 hours excrement The amount (% dosage) of detected peptide 993.

Figure 12 A-12D are summarized will use prednisolone (prodnisolone) or anti-in the TNBS models of acute colitis The systemic treatment of IL-23p19 neutralizing antibodies and the experiment being compared by the way that the treatment of peptide 993 is administered orally.Figure 12 A are shown Changes of weight (percentage) of the rat that sham-operation, medium and peptide 993 are handled from the 0th day to the 7th day.Figure 12 B are shown In the ratio between the colon weight for the colon that the 7th day harvests from rat and colon lengths (based on mg/cm).Figure 12 C were shown at the 7th day The colon Macroscopic score of the colon harvested from rat.Figure 12 D, which are shown, is derived from the rat that sham-operation, medium and peptide 993 are handled Colon histopathological scores summation.For all experiments, the statistics ratio between carrying out group with one-way analysis of variance Compared with then carrying out post-hoc tests：* p ＜ 0.05；* p ＜ 0.01；* * p ＜ 0.001；* * * p ＜ 0.0001；Ns, not significantly.

Figure 13 A-13C, which are summarized, will use in prednisolone or anti-IL-23 p 19 and resist in the TNBS models of acute colitis The systemic treatment of body and the experiment being compared by the way that the treatment of peptide 1185 is administered orally.Figure 13 A show sham-operation, medium Changes of weight (percentage) of the rat that object and peptide 1118 are handled from the 0th day to the 7th day.Figure 13 B are shown at the 7th day from rat The ratio between the colon weight of the colon of harvest and colon lengths (based on mg/cm).Figure 13 C, which are shown, to be harvested from rat at the 7th day The colon Macroscopic score of colon.For all experiments, the statistics between carrying out group with one-way analysis of variance compares, and then carries out Post-hoc tests：* p ＜ 0.05；* p ＜ 0.01；* * p ＜ 0.001；* * * p ＜ 0.0001；Ns, not significantly.

Figure 14 A-14D, which are summarized, will use in prednisolone or anti-IL-23 p 19 and resist in the TNBS models of acute colitis The systemic treatment of body and the experiment being compared by the way that the treatment of peptide 980 is administered orally.Figure 14 A show sham-operation, medium Changes of weight (percentage) of the rat that object and peptide 980 are handled from the 0th day to the 7th day.Figure 14 B are shown at the 7th day from rat The ratio between the colon weight of the colon of harvest and colon lengths (based on mg/cm).Figure 13 C, which are shown, to be harvested from rat at the 7th day The colon Macroscopic score of colon.Figure 14 D show the tissue for the colon for being derived from the rat that sham-operation, medium and peptide 980 are handled The summation of histological scores.For all experiments, statistics compares between carrying out group with one-way analysis of variance, then carries out subsequent It examines：* p ＜ 0.05；* p ＜ 0.01；* * p ＜ 0.001；* * * p ＜ 0.0001；Ns, not significantly.

Figure 15 A-15E show in sham-operation (not being that TNBS exposes) experimental group or receive medium or the processing of peptide 993 TNBS exposures experimental group in rat colon in measured disease and the biomarker for IL-23 level. Show the number for MPO (Figure 15 A), IL-6 (Figure 15 B), IL-1 β (Figure 15 C), IL-22 (Figure 15 D) and IL-17A (Figure 15 E) According to.For all experiments, statistics compares between carrying out group with one-way analysis of variance, then carries out post-hoc tests：* p ＜ 0.05；* p ＜ 0.01；* * p ＜ 0.001；* * * p ＜ 0.0001；Ns, not significantly.

Figure 16 A-16B show in sham-operation (not being that TNBS exposes) experimental group or receive medium or the processing of peptide 980 TNBS exposures experimental group in rat colon in measured disease and the biomarker for IL-23 level. Show the data for MPO (Figure 16 A) and IL-22 (Figure 16 B).For all experiments, group is carried out with one-way analysis of variance Between statistics compare, then carry out post-hoc tests：* p ＜ 0.05；* p ＜ 0.01；* * p ＜ 0.001；* * * p ＜ 0.0001； Ns, not significantly.

Figure 17 A-17D show the Schild analyses of inhibitor peptide.Figure 17 A show that description has the peptide in following concentration Chart in the presence of 993 as the %Emax of the function of cumulative IL-23 concentration responses：0nM (filled circles), 0.3nM (solid squares Block), 1nM (triangle), 3nM (up-side down triangle), 10nM (diamond shape), 30nM (open circles) or 100nM (hollow square).Curve Property is listed under chart.Figure 17 B depict from same group of experiment as a result, and showing to show and making on a log scale For the Log (dose ratios of the function of 993 concentration of peptide (M)^-1) chart.The property of the linear function generated is shown under chart.Figure 17C shows that description has the SEQ ID NO in following concentration：Function in the presence of 1169 peptide as cumulative IL-23 concentration %Emax response chart：0nM (filled circles), 0.3nM (closed square), 1nM (triangle), 3nM (up-side down triangle), 10nM (diamond shape), 30nM (open circles) or 100nM (hollow square).The property of curve is listed under chart.Figure 17 D show that description has The SEQ ID NO of following concentration：Figure in the presence of 1211 peptide as the %Emax of the function of cumulative IL-23 concentration responses Table：0nM (filled circles), 0.3nM (closed square), 1nM (triangle), 3nM (up-side down triangle), 10nM (diamond shape), 30nM are (hollow Circle) or 100nM (hollow square).The property of curve is listed under chart.

Figure 18 A-18B show the pharmacokinetic data of IL-23R inhibitor peptides peptide 1185.Figure 18 A are shown in blood plasma And it is derived from the concentration of the peptide 1185 in the sample of small intestine and colon.Twenty-four-hour urine liquid neutralizes after Figure 18 B show oral administration The amount (% dosage) of detected peptide 1185 in excrement.

Figure 19 A and 19B show the pharmacokinetic data of IL-23R inhibitor peptides peptide 980.Figure 19 A are shown in blood plasma And it is derived from the concentration of the peptide 980 in the sample of small intestine and colon.Figure 19 B are shown after oral administration in twenty-four-hour urine liquid and excrement Just the amount (% dosage) of detected peptide 980 in.

Detailed description of the invention

Unless otherwise defined herein, the scientific and technical terms used in this application should have ordinary skill people The normally understood meaning of member.In general, in conjunction with chemistry, molecular biology, cell and carcinobiology described herein, being immunized The nomenclature that, microbiology, pharmacology and protein and nucleic acid chemistry use, and chemistry, molecular biology, cell and The technology of carcinobiology, immunology, microbiology, pharmacology and protein and nucleic acid chemistry is it is well known that and common 's.

As it is used herein, following terms, which have, assigns their meaning, unless otherwise indicated.

Throughout the specification, word " including (comprise) " or its variant such as " comprising (comprises) " or " include (comprising) " it is understood to mean comprising the integer (or component) or integer (or component) group, but does not arrange Except any other integer (or component) or integer (or component) group.

Singulative " one/one kind (a) ", " one/one kind (an) " and " (the) " includes plural number, unless up and down Text is otherwise explicitly indicated.

Term " comprising " is used for meaning " to include but not limited to "." comprising " and " including but not limited to " are used interchangeably.

Term " patient ", " object " and " individual " is used interchangeably, and refers to people or non-human animal.These terms include feeding Newborn animal, if people, primate, livestock animals (for example, bovid, porcine animals), companion animal are (for example, canid, cat Section animal) and rodent (for example, mouse and rat).

Terms used herein " peptide " broadly refer to the sequence that two or more amino acid are linked together by peptide bond Row.It should be understood that the term had not both implied that the amino acid polymer of specific length, it is not intended to hint or distinguishes whether polypeptide makes With recombinant technique, chemical synthesis or enzymatic synthesis generate or whether be naturally occurring.

Statement " sequence identity " used herein, " homogeneity percentage ", " percent homology " or for example comprising " with ... 50% same sequence " refer to the sequence phase based on nucleotide and nucleotide or amino acid and amino acid in comparison window Same degree.Therefore, " Percentage of sequence identity " can calculate in the following way：Compare two in comparison window most preferably The sequence of comparison measures the identical nucleic acid base (for example, A, T, C, G, I) or same amino acid residue occurred in the two sequences (for example, Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys and Met) position number to obtain matched position number, it is total with matched position number divided by comparison window Positional number (i.e. window size), by the result multiplied by with 100 to obtain Percentage of sequence identity.Can carry out as follows sequence it Between sequence similarity or sequence identity (term is used interchangeably herein) calculating.In order to measure two amino acid The homogeneity percentage of sequence or two nucleic acid sequences the sequence can be compared for best omparison purpose (for example, being Vacancy, can be introduced in the one or both in the first and second amino acid or nucleic acid sequence by best alignment；And for than Compared with purpose, non-homogeneous sequence can be ignored).In certain embodiments, the canonical sequence being compared for comparative purposes Length be at least the 30% of the canonical sequence length, preferably at least 40%, more preferably at least 50%, 60%, and even More preferably at least 70%, 80%, 90%, 100%.Then the amino acid compared in corresponding amino acid position or nucleotide position is residual Base or nucleotide.When the position in First ray by with the same amino acid residue or nucleosides in the corresponding position of the second sequence When acid occupies, then molecule is identical in the position.

Homogeneity percentage between two sequences be the shared same position number of sequence (by for two sequences most Good alignment and the number in vacancy and the length in each vacancy that must be introduced into are taken into account) function.

Sequence between mathematical algorithm being used to complete two sequences compares the measurement with homogeneity percentage.At some In embodiment, using in the GAP programs being incorporated into GCG software packages Needleman and Wunsch algorithms (1970, J.Mol.Biol.48：444-453), using 62 matrixes of Blossum or PAM250 matrixes and 16,14,12,10,8,6 or 4 Gap weight and 1,2,3,4,5 or 6 Length Weight, to measure the homogeneity percentage between two amino acid sequences.And In another preferred embodiment of the present, using the GAP programs in GCG software packages, using NWSgapdna.CMP matrixes and 40,50, 60,70 or 80 gap weight and 1,2,3,4,5 or 6 Length Weight, to measure the homogeneity between two nucleotide sequences Percentage.The parameter setting of another exemplary includes 62 score matrixes of Blossum, gap penalty 12, and gap extension penalties are 4 and frameshift gap point penalty be 5.The E.Meyers and W.Miller for being incorporated into ALIGN programs (2.0 editions) can also be used Algorithm (1989, Cabios, 4：11-17), using PAM120 weight residue tables, GAP LENGTH PENALTY 12 and gap penalty 4, To measure two homogeneity percentages between amino acid or nucleotide sequence.Peptide sequence described herein may be used as " looking into Ask sequence " public database is scanned for, for example, to identify other family members or correlated series.It can use Altschul et al. (1990, J.Mol.Biol, 215：NBLAST and XBLAST programs (2.0 editions) 403-10) carry out such search Rope.NBLAST programs, score=100, word length=12 can be used to carry out BLAST nucleotide searches to obtain the core with the present invention The homologous nucleotide sequence of acid molecule.Can use XBLAST programs, score=50, word length=3 carry out BLAST protein searches with Obtain the amino acid sequence homologous with the protein molecular of the present invention.In order to obtain vacancy comparison for comparative purposes, can adopt With such as Altschul et al. (Nucleic Acids Res.25：3389-3402,1997) the Gapped BLAST described in.When When using BLAST and Gapped blast programs, the default ginseng of respective program (for example, XBLAST and NBLAST) can be used Number.Terms used herein " conservative replaces " indicate that one or more amino acid are replaced by another biology kind like residue.It is real Example includes the substitution of the amino acid residue with similar characteristics, for example, p1 amino acid, acidic amino acid, polar amino acid, alkalinity Amino acid, hydrophobic amino acid and aromatic amino acid.See, e.g., following table.In some embodiments of the present invention, one A or multiple Met residues are replaced by nor-leucine (Nle), and the nor-leucine is the bioisostere of Met, but with Met is on the contrary, be not easy to be aoxidized.Conservative is carried out with the residue being generally not present in endogenic mammalian-derived peptides and protein Another example of substitution is with for example, ornithine, canavanine, aminoethylcysteine or another basic amino acid conservative take For Arg or Lys.In some embodiments, one or more of peptide analogues of the invention cysteine can be another Residue such as serine replaces.About the other information of the Phenotypic silence substitution in peptide and protein, see, e.g., Bowie etc. People .Science 247,1306-1310,1990.In scheme below, by physicochemical characteristics to the conservative of amino acid Substitution is grouped.I：Neutral, hydrophilic, II：Acid and amide, III：Alkalinity, IV：It is hydrophobic, V：It is aromatic Bulky amino acid.

I	II	III	IV	V
					A	N	H	M	F
S	D	R	L	Y
					T	E	K	I	W
P	Q		V
					G			C

In scheme below, the conservative replaces of amino acid are grouped by physicochemical characteristics.VI：Neutral Or hydrophobic, VII：Acid, VIII：Alkalinity, IX：It is polar, X：It is aromatic.

VI	VII	VIII	IX	X
					A	E	H	M	F
L	D	R	S	Y
					I		K	T	W
P			C
					G			N
V			Q

Terms used herein " amino acid " or " arbitrary amino acid " refer to arbitrary and all amino acid, including naturally occurring Amino acid (for example, a- amino acid), non-natural amino acid, the amino acid of modification and non-natural amino acid.It includes D- amino acid And l-amino acid.Natural amino acid includes those of naturally occurring amino acid, e.g., for example, being combined as peptide chain to form a large amount of eggs 23 kinds of amino acid of the structural unit of white matter.These amino acid are mainly L stereoisomers, although minority D- amino acid is present in In Bacterial envelope and some antibiotic.20 kinds of " standard " natural amino acids are listed in table above." non-type " day Right amino acid is pyrrolysine (being present in the organism and other eucaryotes of methane phase), selenocysteine (exists In many non-eucaryotes and most of eucaryotes) and N-formylmethionine (by bacterium, mitochondria and chloroplaset Initiation codon AUG coding)." non-natural (Unnatural) " or " non-natural (non-natural) " amino acid right and wrong Proteinogenic amino acids (that is, naturally encode or those of be not present in genetic codon), are abiogenous Or it is chemically synthesized.More than 140 kinds non-natural amino acid are known, and thousands of kinds of more combinations are possible 's.The example of " non-natural " amino acid includes beta-amino acids (β³And β²), homoamino acid, proline and pyruvate derivative, 3- take Alanine derivatives, glycine derivative, the ring-in generation substituted phenylalanine and tyrosine derivative, linear core amino acid, Diamino acid, D- amino acid, Alpha-Methyl amino acid and N- methylamino acids.Non-natural or non-natural amino acid further includes modification Amino acid." modification " amino acid includes being modified by sulphation with comprising the group or Division of Chemistry being naturally not present on amino acid The amino acid (for example, natural amino acid) divided.According to certain embodiment, inhibitor peptides include and are present in the inhibitor peptides Two amino acid residues between intramolecular bond.It should be understood that compared with when not bonding together, when bonding together, institute is formed The amino acid residue for stating key slightly changes.The specific amino acid referred to mean include its nonbonding and bond styles the amino Acid.For example, the amino acid residue homoserine (hSer) or homoserine (Cl) when nonbonding form are participated according to institute of the present invention When the intramolecular bond stated, the form of 2-amino-butyric acid (Abu) may be used.The present invention is included between X4 and X9 containing crosslinked Inhibitor peptides, and crosslinked inhibitor peptides are not contained between X4 and X9, for example, before being cross-linked to form.Therefore, title HSer and Abu is intended to indicate same monoamino-acid and is used interchangeably.

In most cases, the title of used herein naturally occurring and non-naturally occurring aminoacyl residue follows The naming convention proposed by IUPAC organic chemistry naming committee and the biochemical nomenclature commission IUPAC-IUB, such as " α-ammonia The name (Nomenclature of α-Amino Acids) (Recommendations, 1974) of base acid " Biochemistry, 14 (2), described in (1975).If the amino acid that uses in the specification and the appended claims and aminoacyl residue Title and abbreviation degree and indicated difference, then will get across to reader.Some abbreviations for describing the present invention are fixed Justice is in following table 1 A.

Table 1A. non-natural amino acids and chemical part abbreviation (for amino acid derivativges, all L, unless there are rule It is fixed)

Throughout the specification, except non-naturally occurring amino acid refers to (such as alanine, essence by their full name Propylhomoserin etc.), otherwise they are specified by conventional trigram or one-letter abbreviations (such as alanine, for Ala or A；For Arginine is Arg or R, etc.).Unless otherwise stated, the trigram and one-letter abbreviations of amino acid refer to the ammonia in discussing The L- isomeric forms of base acid.Terms used herein " l-amino acid " refer to " L " isomeric forms of peptide, on the contrary, art Language " D- amino acid " refers to " D " isomeric forms of peptide (for example, Dasp, (D) Asp or D-Asp；Dphe, (D) Phe or D- Phe).The amino acid residue of D isomeric forms may replace arbitrary l-amino acid residue, as long as the peptide retains desired work( Energy.When being referred to using one-letter abbreviations, D- amino acid can use lowercase letter as usual.

In the case of not common amino acid or non-naturally occurring amino acid, unless they are referred to by its full name (such as sarcosine, ornithine etc.), otherwise for its residue, using common three character codes or four character code, including, Sar or Sarc (sarcosine, i.e. sarcosine), Aib (α-aminoacid), Dab (2,4-diamino-butanoic), Dapa (2,3- diaminopropionic acid), γ-Glu (gamma-glutamic acid), Gaba (γ-aminobutyric acid), β-Pro (pyrrolidines -3- carboxylic acids) and 8Ado (8- amino -3,6- dioxaoctanoic acid), Abu (2-amino-butyric acid), β hPro (the high proline of β -), β hPhe (the high phenylpropyl alcohols of β - Propylhomoserin) and Bip (β, β diphenylalamine) and Ida (iminodiacetic acid).

Technical staff is it is clear that peptide sequence disclosed herein is shown from left to right, and wherein the left end of sequence is peptide The ends N-, the right end of sequence is the ends C- of peptide.Sequence disclosed herein is in aminoterminal (ends N-) incorporation part " Hy- " of sequence And in c-terminus (ends the C-) incorporation "-OH " part of sequence or "-NH₂" part sequence.In such cases, and unless Be otherwise noted, otherwise discuss in sequence the ends N- " Hy- " part indicate hydrogen atom, correspond to N- end dissociatives primary amino group or The presence of secondary amino group, and "-the OH " or " NH at the ends C- of sequence₂" hydroxyl or amino are partly indicated respectively, correspond to the acyl at the ends C- Amino (CONH₂) presence.In each sequence of the present invention, the ends C- "-OH " partly may replace the ends C- "-NH₂" part, otherwise also So.

Terms used herein " DRP " refer to the peptide rich in disulphide.

Terms used herein " dimer " broadly refer to include the peptide of two or more monomelic subunits.Certain dimerization Body includes two DRP.The dimer of the present invention includes homodimer and heterodimer.The monomelic subunit of dimer can be It is connected at its end C- or the ends N- or it can be connected via internal amino acid residue.Each monomelic subunit of dimer can lead to Same site connection is crossed, or can respectively be connected by different loci (for example, the ends C-, the ends N- or internal site).

Terms used herein " NH₂" it can refer to the free amine group of the aminoterminal for being present in polypeptide.Terms used herein " OH " can refer to the free carboxy for the c-terminus for being present in peptide.In addition, terms used herein " Ac " refer to through the ends C- of polypeptide or The acylated acetyl group protection formed at the ends N-.In certain peptides shown in this article, NH₂Amino is indicated positioned at the ends C- of peptide.

Terms used herein " carboxyl " refer to-CO₂H。

Terms used herein " isostere substitute ", which refer to, has the chemistry and/or architectural characteristic similar with designated amino acid Arbitrary amino acid or other analog parts.

Terms used herein " cyclisation " refer to such reaction：Wherein a part for peptide molecule and the peptide molecule Another part connects to form close ring, such as by forming disulphide bridges or other similar keys.

Terms used herein " subunit ", which refer to, is bonded to form one of a pair of of polypeptide monomer of dimer peptide composition.

Terms used herein " junction portion " broadly refer to connect or be incorporated in one by two peptide monomer subunits It rises to form the chemical constitution of dimer.

Terms used herein " pharmaceutically acceptable salt " indicate the peptide of the present invention or the salt or amphoteric ion shape of compound Formula is suitable for the treatment of disease for water-soluble or oil-soluble or dispersible, and without excessive toxicity, irritation and mistake Quick reaction；It matches with rational benefit/risk ratio, and it is effective for their desired use.The salt can be with It prepares during the final separation and purifying of compound, or is prepared separately by making amino be reacted with suitable acid.It is representative Acid-addition salts include acetate, adipate, alginates, citrate, aspartate, benzoate, benzene sulfonate, sulphur Sour hydrogen salt, butyrate, camphor hydrochlorate, camsilate, double gluconates, glycerophosphate, Hemisulphate, enanthate, caproic acid Salt, formates, fumarate, hydrochloride, hydrobromate, hydriodate, 2- hydroxyethanesulfonic acids salt (isethionate), Lactate, maleate, sym-toluenesulfonic acid salt, mesylate, naphthalene sulfonate (naphthylenesulfonate), niacin Salt, 2- naphthalene sulfonates, oxalates, embonate, pectate, persulfate, 3- phenylpropionic acids salt, picrate, new penta Hydrochlorate, propionate, succinate, tartrate, three chloro- acetates, trifluoroacetate, phosphate, glutamate, bicarbonate Salt, tosilate and undecanoate.Also, the amino in the compound of the present invention can be with following quaternized：Methyl, Ethyl, the chloride of propyl and butyl, bromide and iodide；The sulfuric ester of dimethyl, diethyl, dibutyl and diamyl； Chloride, bromide and the iodide of decyl, dodecyl, myristyl and sterol base；And the bromination of benzyl and phenethyl Object.The example that the acid for the treatment of acceptable addition salt can be used for being formed includes the nothing of such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid Machine acid, and such as oxalic acid, maleic acid, succinic acid and citric acid organic acid.Pharmaceutically acceptable salt can suitably for The salt such as selected in acid-addition salts and basic salt.The example of acid-addition salts includes chloride salt, citrate and acetate.Alkali The example of formula salt includes such salt：Wherein cation is selected from alkali metal cation, such as calcium of such as sodium ion or potassium ion The alkaline earth metal cation of ion or magnesium ion and the ammonium ion of substitution, such as the ion of N (R1) (R2) (R3) (R4)+type, Wherein R1, R2, R3 and R4 are mostly independently appointed as hydrogen, the C1-6- alkyl optionally replaced or the C2-6- alkenyls optionally replaced. The example of relevant C1-6- alkyl includes methyl, ethyl, 1- propyl and 2- propyl.The example packet of possible relevant C2-6- alkenyls Include vinyl, 1- acrylic and 2- acrylic.Other examples of pharmaceutically acceptable salt are described in " Remington pharmaceutical science (Remington ' s Pharmaceutical Sciences) ", the 17th edition, Alfonso R.Gennaro (Ed.), Mark Publishing Company, Easton, PA, USA, 1985 (and its more recent version) are described in " medical science encyclopedia (Encyclopaedia of Pharmaceutical Technology) ", the 3rd edition, James Swarbrick (Ed.), Informa Healthcare USA (Inc.), NY, USA, 2007, and it is described in J.Pharm.Sci.66：In 2 (1977). Also, about the summary of suitable salt, referring to the Handbook of Pharmaceutical write by Stahl and Wermuth Salts：Properties, Selection, and Use (Wiley-VCH, 2002).Other suitable alkali salts are made of alkali, Form nontoxic salts.Representative example includes aluminium salt, arginine salt, tardocillin salt, calcium salt, choline salt, diethylamine salt, diethyl Alcohol amine salt, glycinate, lysine salt, magnesium salts, meglumine salt, ethanolamine salt, sylvite, sodium salt, amino butanetriol salt and zinc salt. Half salt of bronsted lowry acids and bases bronsted lowry can be formed, for example, Hemisulphate and half calcium salt.

Terms used herein " N (α) methylates " describe methylating for the α amine of amino acid, are also usually called N- first Base.

Terms used herein " symmetrically methylating " or " Arg-Me-sym " describe two nitrogen of arginic guanidine radicals Symmetrically methylate.In addition, term " asymmetry methylates " or " Arg-Me-asym " describe the single nitrogen of arginic guanidine radicals It methylates.

Terms used herein " acylated organic compound " refer to the various compounds with carboxylic acid functional, are used for making ammonia The ends N- of base acid or monomer or dimer (for example, monomelic subunit before forming the ends C- dimer) are acylated.Acylation organises Close object non-limiting examples include Cyclopropylacetic acid, 4- fluobenzoic acids, 4- fluorophenylacetic acids, 3- benzenpropanoic acids, succinic acid, glutaric acid, Cyclopentane-carboxylic acid, 3,3,3- trifluoroacetic acids, 3- methyl fluorides butyric acid, tetrahydrochysene -2H- pyrans -4- carboxylic acids.

Term " alkyl " includes the linear chain or branched chain containing 1 to 24 carbon atom, non-annularity or cricoid saturated aliphatic hydrocarbon. Representative saturated straight chain alkyl includes but not limited to methyl, ethyl, n-propyl, normal-butyl, n-pentyl, n-hexyl etc., and is satisfied The branched hydrocarbyl of sum includes being not limited to, isopropyl, sec-butyl, isobutyl group, tertiary butyl, isopentyl etc..Representative saturated cyclic hydrocarbons Base includes but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc., includes being not limited to without saturated cyclic, cyclopentene Base, cyclohexenyl group etc..

Term " mammal " refers to any Mammalian, such as people, mouse, rat, dog, cat, hamster, cavy, rabbit, domestic animal Deng.

As it is used herein, " therapeutically effective amount " of the inhibitor peptides of the present invention is intended to description treatment IL-23/IL-23R The sufficient amount of the inhibitor peptides of relevant disease (for example, to reduce and the relevant inflammation of IBD), the disease include but not limited to this Arbitrary disease and illness described in text.In a particular embodiment, therapeutically effective amount, which will be realized, is suitable for any therapeutic treatment Expectation benefit/risk ratio.

" analog " of amino acid, for example, " Phe analogs " or " Tyr analogs ", it is intended that the amino acid referred to it is similar Object.A variety of amino acid analogues are known in the art and obtainable, including Phe and Tyr analogs.In certain embodiments In, amino acid analogue, for example, Phe analogs or Tyr analogs relative to Phe or Tyr separately include one, two, three A, four or five substitutions.In certain embodiments, substitution is present in the side chain of amino acid.In certain embodiments, Phe analogs have structure Phe (R²), wherein R²For Hy, OH, CH₃、CO₂H、CONH₂、CONH₂OCH₂CH₂NH₂、t-Bu、 OCH₂CH₂NH₂, phenoxy group, OCH₃, O allyls, Br, Cl, F, NH₂, N3 or guanidine radicals.In certain embodiments, R²For CONH₂OCH₂CH₂NH₂、OCH₃、CONH₂、OCH₃Or CO₂H.The example of Phe analogs includes but not limited to：hPhe、Phe(4- OMe), α-Me-Phe, hPhe (3,4- dimethoxy), Phe (4-CONH₂), Phe (4- phenoxy groups), Phe (4- guanidine radicals), Phe (4-tBu)、Phe(4-CN)、Phe(4-Br)、Phe(4-OBzl)、Phe(4-NH₂), BhPhe (4-F), Phe (4-F), Phe (3, 5DiF)、Phe(CH₂CO₂H), Phe (5-F), Phe (3,4-Cl₂), Phe (3,4-F₂)、Phe(4-CF₃), β β-two PheAla, Phe (4-N₃), Phe [4- (2- amino ethoxies)], 4- phenylbenzyls alanine, Phe (4-CONH₂), Phe (3,4- dimethoxy), Phe(4-CF₃), Phe (2,3-Cl₂) and Phe (2,3-F₂).The example of Tyr analogs includes but not limited to：hTyr、N-Me- Tyr、Tyr(3-tBu)、Tyr(4-N₃) and β hTyr.

The inhibitor peptides of IL-23R

Genome-wide association study (GWAS) is proved IL-23 receptor (IL-23R) gene and inflammatory bowel disease (IBD) Important association shows that the disturbance of IL-23 signal transductions may be related with the pathogenesis of the disease.The present invention provides through peptides Oral medication selectivity antagonism IL-23R adjust the composition and method of IL-23 accesses, the peptide is stable and office It is limited to stomach and intestine (GI) tissue.Identify uniquely resistance to oxidation/reduction item in a variety of analyses of multiple compartments of simulation GI environment The novel peptide for inhibiting of part and proteolytic degradation.Functionally, these peptides are effective in the human cell line of conversion and people's primary cell Ground neutralizes the signal transduction that IL-23 is mediated.And the combination of IL-23R is selective, because the peptide does not block IL-6 and IL- Interaction between 6R or antagonism IL-12 signal transduction pathways.Moreover, these peptides delivered by oral administration are weakening 2,4,6- It is effective in colitis in the rat model of the acute IBD of trinitrobenzene sulfonic acid (TNBS) induction, such as passes through the weight of colon Amount and length are more shown than substantially reducing for, colon Macroscopic score, neutrophil cell infiltration and histopathology, and right It is suitable according to anti-IL-23 p 19 mAb.

The present invention relates generally to the peptides with IL-23R antagonist activities comprising peptide monomer and peptide dimer.Certain In embodiment, present invention demonstrates that passing through the antagonist for treating IBD and Other diseases of oral delivery IL-23 and the new model of illness Formula.IBD indicates the local inflammation of intestinal tissue；When therefore, compared with the method with whole body, beneficial therapeutic agent will be opened from enteric cavity side Beginning acts on, and to generate high drug concentration in pathological tissues, so that the availability of whole body is minimized and leads to improved work( Effect and safety.The oral administration expection of the compound of the present invention makes the levels of drugs in the intestinal tissue of lesion maximize, simultaneously Drug concentration in limitation cycle, it is effective, safe and lasting to be provided for the life-long therapy of IBD and Other diseases and illness Delivering.

In certain embodiments, the present invention relates to by disulfide bond or the annellated structure of other key-shapeds various peptides or Including the peptide dimer of heterologous monomer or autohaploid subunit.In certain embodiments, disulfide bond or other keys are intramoleculars Key.Have been displayed the monomelic subunit of peptide monomer inhibitor and peptide dimer inhibitor cyclized structure increase inhibitor peptides effect and Selectivity.In certain embodiments, peptide dimer inhibitor, which may be embodied in, connects two monomers in peptide dimer inhibitor One or more intermolecular linkages of peptide subunit, for example, (there are one half Guang ammonia in each peptide monomer subunit for two cysteine residues Sour residue) between intermolecular bridge.

The present invention provides the inhibitor peptides combined with IL-23R, can be monomer or dimer.In specific embodiment In, inhibitor peptides inhibit the combination of IL-23 and IL-23R.In certain embodiments, IL-23R is people IL-23R and IL- 23 be people IL-23.In certain embodiments, compared with negative control peptide, inhibitor peptides of the invention are by IL-23 and IL-23R Combination reduce at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or extremely Few 90%.It is known in the art to measure the method combined, and includes elisa assay, as described in appended embodiment 's.

In certain embodiments, for example, for inhibiting IL-23 and IL-23R's (for example, human IL-2 3 and human IL-2 3R) In conjunction with the IC50 of inhibitor peptides of the invention is ＞ 1mM, ＜ 1mM, 500nM to 1000nM, ＜ 500nM, ＜ 250nM, ＜ 100nM, ＜ 50nM, ＜ 25nM, ＜ 10nM, ＜ 5nM, ＜ 2nM, ＜ 1nM or ＜ 5mM.Measure active method be this field Know, and includes any one of method those of described in appended embodiment.

In certain embodiments, inhibitor peptides of the invention have increased stability, increased relative to control peptide Stomach and intestine stability or in simulated intestinal fluid (SIF) or simulate the gastric juice (SGF) and/or under Redox Condition (for example, DTT) Increased stability.In certain embodiments, control peptide is the unrelated peptide of same or like length.In specific embodiment In, control peptide is that have identical or highly relevant amino acid sequence (for example, sequence identity of ＞ 90%) with inhibitor peptides Peptide.In a particular embodiment, control peptide is that have identical or highly relevant amino acid sequence (for example, ＞ with inhibitor peptides 90% sequence identity) peptide, but its do not have for example pass through the intramolecular bond between two amino acid residues in it Either it is not Dimerized to the cyclized structure of formation or it does not include for stabilized conjugate.It is being embodied In scheme, the sole difference between inhibitor peptides and control peptide is that the inhibitor peptides include taking for one or more amino acid In generation, one or more amino acid residues are introduced into inhibitor peptides by the substitution, wherein the amino residue and inhibitor peptides that introduce In another amino acid residue formed sulfide in disulfide bond or thioether bond.One example of the control of peptide dimer inhibitor It is that there is mutually homotactic monomer with one of the monomelic subunit being present in peptide dimer inhibitor.Including the peptide of conjugate inhibits One example of the control of agent is that have identical sequence but the peptide not comprising conjugation moiety.In certain embodiments, control peptide Correspond to the peptide (for example, naturally occurring peptide) in the regions IL-23 combined with IL-23R.

The method for measuring the stability of peptide is known in the art.In certain embodiments, it is analyzed using SIF and measures peptide The stability of inhibitor, for example, as described in example 3 above.In certain embodiments, it is analyzed using SGF and measures peptide inhibition The stability of agent, for example, as described in example 3 above.In a particular embodiment, when inhibitor peptides be exposed to SIF or SGF or When DTT, have under one group of given condition (for example, temperature) more than 1 minute, more than 10 minutes, more than 20 minutes, be more than 30 minutes, half-life period more than 60 minutes, more than 90 minutes, more than 120 minutes, more than 3 hours or more than 4 hours (for example, In SIF or SGF or DTT).In certain embodiments, temperature is about 25 DEG C, about 4 DEG C or about 37 DEG C and pH is physiological pH, Or pH is about 7.4.

In some embodiments, using any suitable method known in the art, half-life period, example are measured in vitro Such as, in some embodiments, the stability of peptide of the invention by by the peptide and the human serum of preheating (Sigma) in 37 DEG C It is incubated to measure.Point sampling in different times, usually until 24 hours, and by by peptide or peptide dimer and haemocyanin Then separation analyzes the presence of purpose peptide or peptide dimer to analyze the stability of sample using LC-MS.

In some embodiments, compared with control peptide, improved dissolubility or improvement is presented in inhibitor peptides of the invention Aggregation properties.Dissolubility can be measured via any suitable method known in the art.In some embodiments, originally The known deliquescent appropriate method of measurement in field includes by peptide in a variety of buffer solutions (acetate pH4.0, acetate pH5.0, phosphorus Hydrochlorate/citrate pH5.0, Phosphate Citrate pH6.0, phosphate pH 6.0, phosphate pH 7.0, phosphate pH7.5, Strong PBS pH 7.5, Tris pH7.5, Tris pH 8.0, glycine pH 9.0), water, acetic acid (pH 5.0 and known in the art It is other) in be incubated and using standard technique test aggregation or dissolubility.These standard techniques include but not limited to for example Precipitation, dynamic light scattering, circular dichroism and fluorescent dye are visualized with measurement surface hydrophobicity, and detection of aggregation or fibrinogen Change.In some embodiments, improved dissolubility means compared with control peptide, and the peptide is more solvable in given liquid. In some embodiments, improved aggregation means that compared with control peptide, the peptide is in given liquid under the conditions of given one group There is less aggregation in body.

In certain embodiments, when oral delivery, inhibitor peptides of the invention are stable in stomach and intestine (GI) environment , be conducive to realize high compound concentration in intestinal tissue.In the roads GI proteolysis metabolism by enzyme (including pepsin, Trypsase, chymotrypsin, elastoser, aminopeptidase and Carboxypeptidase A/B) drive, the enzyme from pancreatic secretion to inner cavity or Person generates as brush border enzyme.Protease usually peptide and protein of the cutting in extended conformation.Under the reducing environment of intestinal juice, Disulfide bond can be destroyed, and generate linear peptides and quick proteolysis.Mainly by Cys/CySS redox cycles come really The redox environment of the fixed chamber.In enterocyte, relevant activity is related to many digestive ferments, such as CYP450 and UDP-glucose Aldehydic acid base-transferase.Finally, with 10¹⁰-10¹²The concentration of CFU/ml is present in the bacterium in large intestine and forms another metabolism barrier. In certain embodiments, inhibitor peptides are stable to a variety of pH, highly acid (the pH 1.5- in the ranging from stomach of the pH 1.9), the faintly acid (pH 5-7) tended in alkaline (pH 6-7.5) and colon in small intestine.Such inhibitor peptides are passed through at it (process for being expended 3-4 hours in intestines according to estimates and expending 6-48 hours in colon) is stable during crossing multiple GI compartments 's.

In some embodiments, compared with control peptide, inhibitor peptides of the invention for example whithin a period of time have compared with Few degradation (that is, larger stability to degradation), for example, be more than or about 10% less degradation, be more than or about 20% it is less Degrade, be more than or about 30% less degradation, be more than or about 40% less degradation or be more than or about 50% less drop Solution.In some embodiments, stability to degradation is measured via any suitable method known in the art.In some implementations In scheme, degradation is enzymatic degradation.For example, in certain embodiments, inhibitor peptides are to trypsase, chymotrypsin or elasticity The sensibility of the degradation of protease reduces.In some embodiments, the conjunction known in the art for measuring stability to degradation Suitable method is included in Hawe et al., J Pharm Sci, VOL.101, No.3,2012, the method described in p 895-913, will It is integrally incorporated herein.In some embodiments, such method is used for selecting effective peptide sequence of the half-life period with enhancing. In a particular embodiment, it is analyzed using SIF as described herein or SGF analyzes the stability for measuring peptide.

In certain embodiments, inhibitor peptides of the invention inhibit or reduce the inflammation that IL-23 is mediated.In relevant reality It applies in scheme, thus inhibitor peptides of the invention inhibit IL-23 and cell for example by being combined with the IL-23R on cell surface Combination, come inhibit or reduce IL-23 mediation one or more cell factors secretion.In a particular embodiment, this hair Bright inhibitor peptides inhibit or reduce the activation of Jak2, Tyk2, Stat1, Stat3, Stat4 or Stat5 that IL-23 is mediated.It surveys The method for determining the inhibition of cytokine secretion and the inhibition of signal transducers is known in the art.For example, survey can be passed through The inhibition of phosphorylation-Stat3 levels in amount cell lysate such as exists to measure the inhibition of IL-23/IL-23R signal transductions Described in appended embodiment (including embodiment 2).

In certain embodiments, compared with control peptide, the oxidation-reduction stability of inhibitor peptides increases.It can be used to measure The various analyses of oxidation-reduction stability are known in the art and obtainable.Any one of these can be used for measuring this hair The oxidation-reduction stability of bright inhibitor peptides.

In certain embodiments, the present invention provide it is a variety of combined in vitro or in vivo with IL-23R or associate to destroy or Block the inhibitor peptides of the combination between IL-23 and IL-23R.In certain embodiments, inhibitor peptides combine and/or inhibit Human IL-2 3R.In certain embodiments, inhibitor peptides combine and/or inhibit the IL-23R of people and rodent.In certain implementations In scheme, inhibitor peptides combine and/or inhibit the IL-23R of people and rat.In a particular embodiment, inhibitor peptides are by rat IL-23R inhibit at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% and they tie Human IL-2 3R is closed or inhibits, for example, as measured by analysis described herein.In certain embodiments, with mouse IL-23R is compared, and inhibitor peptides preferentially combine and/or inhibit people and/or rat IL-23R.In a particular embodiment, with mouse IL-23R is compared, and inhibitor peptides are preferentially combined with rat IL-23R.In a particular embodiment, compared with hyperkine R, peptide Inhibitor is preferentially combined with human IL-2 3R.In certain embodiments, the combination of inhibitor peptides and hyperkine R are less than 75% , less than 50%, less than 40%, less than 30%, less than 20% the or same inhibitor peptides less than 10% and people IL- 23R and/or rat IL-23R are combined.Human IL-2 3R and/or rat are preferentially being combined and/or inhibited compared with hyperkine R In certain embodiments of the inhibitor peptides of IL-23R, inhibitor peptides and it is present in hyperkine R but is not present in people IL- The regions IL-23R that the presence of the other amino acid of 23R or rat IL-23 destroys combine.In one embodiment, it is present in Other amino acid in hyperkine R is residual to about amino acid in the about amino acid residue 315 corresponding to mouse IL23R albumen In the region of base 340, for example, amino acid region NWQPWSSPFVHQTSQETGKR (see, e.g. Fig. 4).In specific embodiment party In case, inhibitor peptides are combined with the region of about amino acid 230 to the human IL-2 3R of about amino acid residue 370.

In certain embodiments, inhibitor peptides show the restricted positioning of GI after oral administration.In specific embodiment In, the inhibitor peptides of the oral administration more than 50%, more than 60%, more than 70%, more than 80% or more than 90% are positioned To gastrointestinal organ and tissue.In a particular embodiment, the blood plasma level of the inhibitor peptides of oral administration is less than 20%, small It is in 10%, less than 5%, less than 2%, less than 1% or less than 0.5% be present in mucous membrane of small intestine, mucous membrane of colon or Inhibitor peptides in proximal colon are horizontal.

The various inhibitor peptides of the present invention can be only made of natural amino acid.Optionally, inhibitor peptides can include non- Natural amino acid, the non-natural amino acid include but not limited to the amino acid modified.In certain embodiments, the ammonia of modification Base acid includes the natural amino acid to include the group or chemical part that are not naturally occurring on amino acid through chemical modification.This hair Bright inhibitor peptides can additionally comprise one or more D- amino acid.Further, inhibitor peptides of the invention can include Amino acid analogue.

In certain embodiments, inhibitor peptides of the invention include one or more modifications or non-natural amino Acid.For example, in certain embodiments, inhibitor peptides include one or more below：Dab、Dap、Pen、Sarc、Cit、 Cav、hLeu、2-Nal、D-1-Nal、D-2-Nal、Phe(4-OMe)、βhTrp、α-MePhe、α-MeTyr、α-MeTrp、β- HPhe、Phe(4-CF₃), 2-2- indanes, 1-1- indanes, cyclobutyl, β-hPhe, Gla, Phe (4-NH₂)、hPhe、1-Nal、Nle、 Homoamino acid, D- amino acid, 4,4 '-biphenylalanines (Bip), cyclobutyl-Ala, hCha, β hPhe, β Glu, Phe (4- guanidines Base), Phe [4- (2- amino ethoxies)], Phe [4- (2- acetylaminos ethyoxyl)], Phe (4-CONH₂)、Phe(4-Me)、 Tyr (Bzl) or Tyr (Me), Phe (3,4- bis- F₂), Phe (3,4-Cl₂), Phe (3-Me), Phe [4- (2- amino ethoxies)], Phe [4- (2- acetylaminos ethyoxyl)], Phe (Br), Phe (4-CONH₂), Phe (Cl), Phe (4-CN), Phe (4- guanidine radicals), Phe(4-Me)、Phe(4-NH₂), Phe (4-N3), Tyr, Tyr (Bzl) or Tyr (Me), Phe (3,4- dimethoxy), 5- hydroxyls Trp, Phe (3,4-Cl₂), Tyr (3-tBu) and various N- methylated amino-acids and Alpha-Methyl amino acid.The one of the present invention In a little embodiments, inhibitor peptides include one or more non-natural amino acids shown in table 1A.Those skilled in the art manage In addition solution is modified or non-natural amino acid, and with modification or non-natural amino acid natural amino acid is carried out it is more Similar expected result may be implemented in a other substitutions, and such is substituted in the teachings of the present invention and spirit.In certain realities It applies in scheme, inhibitor peptides of the invention include any one of inhibitor peptides those of described herein comprising but it is unlimited The amino acid sequence shown in the either table comprising this paper, the sequence table of accompanying or attached drawing or the peptide of inhibitor peptides structure inhibit Any one of agent, amino acid substitution that wherein one or more residues are modified or non-natural.

The invention also includes the arbitrary inhibitor peptides described herein in free or salt form.Therefore, it is retouched herein The embodiment (and application thereof correlation technique) for the arbitrary inhibitor peptides stated includes the pharmaceutically acceptable salt of inhibitor peptides.

The invention also includes the variants of arbitrary inhibitor peptides described herein comprising but it is not limited to this paper's Any one of those of sequence, wherein one or more L- shown in any of table, the sequence table of accompanying or attached drawing Amino acid residue is replaced by the D isomeric forms of the amino acid residue, for example, L-Ala is replaced by D-Ala.

In the specific embodiment of inhibitor peptides described herein, they include one or more non-natural or non-days Right amino acid residue.

The invention also includes the arbitrary peptide monomer inhibitor described herein of jointing part, the connector portions subpackages Include arbitrary specific linkers part described herein.In a particular embodiment, connector is connect with the ends N- or C-terminal amino acid, And in other embodiments, connector is connect with internal amino acid.In a particular embodiment, connector and two internal amino acids Connection, for example, forming the internal amino acid in each of two monomelic subunits of dimer.In some embodiments of the present invention In, inhibitor peptides one or more junction portions with shown in are connect.

The invention also includes comprising with the peptide sequence of inhibitor peptides described herein have at least 90%, at least 95%, The peptide and peptide dimer of the peptide of at least 98% or at least 99% sequence identity.In a particular embodiment, peptide of the invention Inhibitor includes Core peptide sequence and one or more N-terminals and/or C-terminal modification (such as Ac and NH₂) and/or one or more sew The junction portion of conjunction and/or half-life extension moiety.As used herein, Core peptide sequence is that such modification and conjugate is not present Peptide amino acid sequence.For example, for inhibitor peptides：[Palm]-[different Glu]-[PEG4]-[Pen]-NTWQ- [Pen]- [Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂, Core peptide sequence is：[Pen]- NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN.

In certain embodiments, the monomelic subunit of inhibitor peptides of the invention or inhibitor peptides includes following, substantially It is made up of or is made up of：7 to 35 amino acid residues, 8 to 35 amino acid residues, 9 to 35 amino acid residues, 10 to 35 amino acid residues, 7 to 25 amino acid residues, 8 to 25 amino acid residues, 9 to 25 amino acid residues, 10 to 25 amino acid residues, 7 to 20 amino acid residues, 8 to 20 amino acid residues, 9 to 20 amino acid residues, 10 to 20 Amino acid residue, 7 to 18 amino acid residues, 8 to 18 amino acid residues, 9 to 18 amino acid residues or 10 to 18 ammonia Base acid residue and optionally, one or more other non-amino acid parts, such as conjugated chemical part, for example, PEG or Junction portion.In a particular embodiment, inhibitor peptides of the invention (or monomer subunit) (include but not limited to Formula X, Formulas I, Formula II, formula III, formula IV or Formula V any embodiment in those of) be more than 10 amino acid, more than 12 amino acid, be more than 15 amino acid are more than 20 amino acid, are more than 25 amino acid, are more than 30 amino acid or are more than 35 amino acid, for example, For 35 to 50 amino acid.In certain embodiments, inhibitor peptides (or monomer subunit) are less than 50 amino acid, are less than 35 A amino acid is less than 30 amino acid, is less than 25 amino acid, is less than 20 amino acid, is less than 15 amino acid, is less than 12 Amino acid is less than 10 amino acid.In a particular embodiment, the monomelic subunit packet of inhibitor peptides (or peptide monomer inhibitor) Containing following or be made up of：7,8,9,10,11,12,13,14,15,16,17,18, 19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34 A or 35 amino acid residues.In a particular embodiment, the monomelic subunit of inhibitor peptides of the invention include it is following or by with Lower composition：10 to 18 amino acid residues and, optionally, one or more other non-amino acid parts, such as conjugated change The department of the Chinese Academy of Sciences point, for example, PEG or junction portion.In different implementation scenarios, monomelic subunit includes following or is made up of：7 to 35 amino acid residues, 7 to 20 amino acid residues, 8 to 20 amino acid residues, 9 to 20 amino acid residues, 10 to 20 Amino acid residue, 8 to 18 amino acid residues, 8 to 19 amino acid residues, 8 to 18 amino acid residues, 9 to 18 amino Sour residue or 10 to 18 amino acid residues.It is described herein it is various in the specific embodiment of any one, X include with Down or it is made up of：7 to 35 amino acid residues, 8 to 35 amino acid residues, 9 to 35 amino acid residues, 10 to 35 Amino acid residue, 7 to 25 amino acid residues, 8 to 25 amino acid residues, 9 to 25 amino acid residues, 10 to 25 amino Sour residue, 7 to 18 amino acid residues, 8 to 18 amino acid residues, 9 to 18 amino acid residues or 10 to 18 amino acid Residue.

Certain exemplary peptides inhibitor described herein include 12 or more amino acid residues.However, of the invention Further include comprising arbitrary peptide sequence described herein segment inhibitor peptides comprising have 7,8,9,10 or The inhibitor peptides of 11 amino acid residues.For example, the inhibitor peptides of the present invention include comprising peptide that is following or being made up of： X4-X9, X4-X10, X4-X11, X4-X12, X4-X13, X4-X14, X4-X15 or X4-X16.In a particular embodiment, this hair Bright includes the inhibitor peptides for having arbitrary sequence described herein comprising but it is not limited to any in formula as described herein Shown in a, sequence table or arbitrary table provided in this article those, wherein X10, X11, X12, X13, X14, X15 or X16 One or more of be not present.In a particular embodiment, one or more of X13, X14, X15 or X16 are not present.

In specific embodiments of the present invention, inhibitor peptides or its area X are not present in antibody.In specific embodiment In, inhibitor peptides or its area X are not present in the V of antibody_HOr V_LIn area.

In a particular embodiment, inhibitor peptides of the invention are cyclized via cyclic amides key, disulfide bond or thioether bond.Having In body embodiment, the key is the intramolecular bond between two amino acid residues in inhibitor peptides or monomer subunit.

Inhibitor peptides

The inhibitor peptides of the present invention include the peptide with any amino acid sequence described herein, with described herein Any structure compound (including the compound for including any peptide sequence described herein) and any such peptide and The dimer of compound.The inhibitor peptides of the present invention are included in the peptide between X4 and X9 without key and have between X4 and X9 There is the peptide of key, for example, between X4 and X9 before and after introducing crosslinked.The exemplary peptides of the present invention include any subordinate list, reality Apply the amino acid sequence or structure described in example, attached drawing and sequence table.

In certain embodiments, the present invention, which includes the inhibitor peptides of Interleukin-23 receptor or its pharmacy, to connect The salt or solvate received, wherein inhibitor peptides include the amino acid sequence of formula (Xa)：

X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19- X20(Xa)

Wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X5 is arbitrary amino acid；

X6 is arbitrary amino acid；

X7 is arbitrary amino acid；

X8 is arbitrary amino acid；

X10 is arbitrary amino acid；

X11 is arbitrary amino acid；

X12 is arbitrary amino acid；

X13 is arbitrary amino acid；

X14 is arbitrary amino acid；

X15 is arbitrary amino acid,

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present,

Wherein X4 and X9 can form key each other.In a particular embodiment, the key is disulfide bond, thioether bond, interior acyl Amine key, triazole ring, selenide key, two selenium keys or alkene key.In a particular embodiment, the key is disulfide bond or thioether bond. In certain embodiments, inhibitor peptides are cyclized via the key between X4 and X9.In certain embodiments, inhibitor peptides inhibit white The combination of cytokine -2 3 (IL-23) and IL-23 receptor.In a particular embodiment, when X4 is not amino acid, then X1, X2 It is not present with X3.In certain embodiments, X1 is D- amino acid or is not present.In certain embodiments, X2 is D- amino Acid is not present.In certain embodiments, X3 is D- amino acid or is not present.In certain embodiments, X16 is D- amino Acid is not present.In certain embodiments, X17 is D- amino acid or is not present.In certain embodiments, X18 is D- ammonia Base acid is not present.In certain embodiments, X19 is D- amino acid or is not present.In certain embodiments, X20 is D- Amino acid is not present.

In an embodiment of the inhibitor peptides of Formula X a,

X1 is not present；

X2 is not present；

X3 is Glu, D-Glu, Arg, (D) Arg, Phe, (D) Phe, 2-Nal, Thr, Leu, (D) Gln or is not present；

X4 is Cys, Abu or Pen；

X5 is Ala, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N- MeArg, Orn, Gln, Arg, Ser or Thr；

X6 is Asp or Thr；

X7 is the chloro- Trp of Trp or 6-；

X8 is Glu, Gln or Val；

X9 is Cys, Abu or Pen；

X10 is 2-Nal, Phe analog, Tyr or Tyr analogs, wherein in a particular embodiment, X10 2-Nal, Phe (3,4- bis- F₂), Phe (3,4-Cl₂), Phe (3-Me), Phe [4- (2- amino ethoxies)], Phe [4- (2- acetylamino second Oxygroup)], Phe (Br), Phe (4-CONH₂), Phe (Cl), Phe (4-CN), Phe (4- guanidine radicals), Phe (4-Me), Phe (4- NH₂), Phe (4-N3), Tyr, Tyr (Bzl) or Tyr (Me)；

X11 is 1-Nal, 2-Nal, Phe (3,4- dimethoxy), 5- hydroxyls Trp, Phe (3,4-Cl₂), Trp or Tyr (3- tBu)；

X12 is 3-Pal, Acpc, Acbc, Acvc, Achc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac)、α-MeLeu、a-α-MeOrn、α-MeSer、α-MeVal、Cav、Cha、Cit、Cpa、D-Asn、Glu、His、hLeu、 HArg, Lys, Leu, Octgly, Orn, piperidines, Arg, Ser, Thr or THP；

X13 be Cit, Asp, Dab, Dap, Phe, His, Dap (Peg2-Ac), Dap (burnt glutaric acid), Glu, hArg, Lys, Lys (Ac), Lys (benzoic acid), Lys (glutaric acid), Lys (IVA), Lys (the different Glu-Palm of Peg4-), Lys (burnt glutaric acid), Lys- succinic acids, Asn, Orn, Gln, Arg, Thr or Val；

X14 is Asp, Dab (Ac), Dap (Ac), Phe, His, Lys (Ac), Met, Asn (isobutyl group), Gln, Arg, Tyr Or Asp (1,4-Diaminobutane)；

X15 be Ala, β Ala, Glu, Gly, Asn, Gln, Arg or Ser,

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present.

In certain embodiments, X3 is not present.In a particular embodiment, X16, X17, X18, X19 and X20 are not deposited .In a particular embodiment, X4 and X9 is Cys, and X4 is connected with X9 via disulfide bond.In a particular embodiment, X4 is Abu and X9 is Pen, and X4 and X9 are keyed via thioether.In a particular embodiment, X4 Abu and X9 For Cys, and X4 and X9 are keyed via thioether.

In the another embodiment of the inhibitor peptides of Formula X a,

X1 is not present；

X2 is not present；

X4 is Cys, Abu or Pen；

X5 be Ala, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, Orn, Gln, Arg, Ser or Thr；

X6 is Asp or Thr；

X7 is the chloro- Trp of Trp or 6-；

X8 is Gln or Val；

X9 is Cys, Abu or Pen；

X10 is 2-Nal, Phe analog, Tyr or Tyr analogs, wherein in a particular embodiment, X10 2-Nal, Phe (3,4- bis- F₂), Phe (3-Me), Phe [4- (2- amino ethoxies)], Phe [4- (2- acetylaminos ethyoxyl)], Phe (Br)、Phe(4-CONH₂), Phe (4-Cl), Phe (4-CN), Phe (4- guanidine radicals), Phe (4-Me), Phe (4-NH₂)、Phe(4- N₃), Tyr, Tyr (Bzl) or Tyr (Me)；

X12 is 3-Pal, Acpc, Acbc, Acvc, Achc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac)、α-MeLeu、α-MeOrn、α-MeSer、α-MeVal、Cav、Cha、Cit、Cpa、D-Asn、His、hLeu、hArg、Lys、 Leu, Octgly, Orn, 4- amino -4- Carboxy-piperidins or THP；

X14 is Dab (Ac), Dap (Ac), Phe, His, Lys (Ac), Met, Asn, Gln, Arg or Tyr；

X15 be Ala, β Ala, Gly, Asn, Gln or Ser,

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present.

In some embodiments, X3 is not present.In a particular embodiment, X16, X17, X18, X19 and X20 are not deposited .In a particular embodiment, X4 and X9 is Cys, and X4 is connected with X9 via disulfide bond.In a particular embodiment, X4 It is Pen for Abu and X9, and X4 and X9 are keyed via thioether.In a particular embodiment, X4 Abu and X9 are Cys, and X4 and X9 are keyed via thioether.

In the another embodiment of the inhibitor peptides of Formula X a,

X1 is not present；

X2 is not present；

X4 is Cys, Abu or Pen；

X5 is Dap, Dap (Ac), Gly, Lys, Gln, Arg, Ser, Thr or Asn；

X6 is Thr；

X7 is the chloro- Trp of Trp or 6-；

X8 is Gln；

X9 is Cys, Abu or Pen；

X10 is 2-Nal, Phe analog, Tyr or Tyr analogs, wherein in a particular embodiment, X10 2-Nal, Phe (3-Me), Phe [4- (2- amino ethoxies)], Phe [4- (2- acetylaminos ethyoxyl)], Phe (4-CONH₂)、Phe(4- Me)、Phe(4-NH₂), Tyr, Tyr (Bzl) or Tyr (Me)；

X11 is 1-Nal, 2-Nal, Phe (3,4- dimethoxy), Phe (3,4-Cl₂) or Trp；

X12 be Acpc, Acbc, Acvc, Achc, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-MeLeu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, hLeu, Lys, Leu, Arg or THP；

X13 is Cit, Asp, Dap, Dap (Peg2-Ac), Dap (burnt glutaric acid), Glu, hArg, Lys, Lys (Ac), Lys (benzoic acid), Lys (glutaric acid), Lys (IVA), Lys (the different Glu-Palm of Peg4-), Lys (burnt glutaric acid), Lys (succinic acid), Asn, Orn, Gln, Arg or Val；

X14 is Dab (Ac), Dap (Ac), His, Lys (Ac), Asn, Gln or Tyr；

X15 be Ala, β Ala, Gly, Asn, Gln or Ser,

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present.

In some embodiments, X3 is not present.In a particular embodiment, X16, X17, X18, X19 and X20 are not deposited .In a particular embodiment, X4 and X9 is Cys, and X4 is connected with X9 via disulfide bond.In a particular embodiment, X4 is Abu and X9 is Pen, and X4 and X9 are keyed via thioether.In a particular embodiment, X4 Abu and X9 For Cys, and X4 and X9 are keyed via thioether.

In the another embodiment of the inhibitor peptides of Formula X a,

X1 is not present；

X2 is not present；

X4 is Cys, Abu or Pen；

X5 is Dap, Dap (Ac), Gln, Ser, Thr or Asn；

X6 is Thr；

X7 is Trp；

X8 is Gln；

X9 is Cys, Abu or Pen；

X10 is Phe analogs, Tyr or Tyr analogs, wherein in a particular embodiment, X10 is Phe [4- (2- amino Ethyoxyl)], Phe [4- (2- acetylaminos ethyoxyl)], Phe (4-CONH₂), Phe (4-Me), Tyr, Tyr (Bzl) or Tyr (Me)；

X11 is 2-Nal or Trp；

X12 be Acpc, Acbc, Acvc, Achc, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-MeLeu, α-MeOrn, α-MeSer, α-MeVal, hLeu, Leu or THP；

X13 is Cit, Asp, Glu, Lys, Lys (Ac), Asn or Gln；

X14 is Dab (Ac), Asn or His；

X15 is Ala, β Ala, Gly, Asn or Gln；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present.

In a particular embodiment, inhibitor peptides include described herein any of various, for example, Ia-It, Amino acid sequence shown in IIa-IId, IIIa-IIIe or IV.

In certain embodiments, the present invention, which includes the inhibitor peptides of Interleukin-23 receptor or its pharmacy, to connect The salt or solvate received, wherein inhibitor peptides have the structure of Formulas I：

R¹-X-R²(I)

Wherein R¹For key, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, C1-C20 hydrocarbon acyl groups, And including any one of aforementioned individual PEGylated forms or as the PEGylated forms of introns；

R²For key, OH or NH₂；And

X is amino acid sequence, for example, including the amino acid of 7 to 35 amino acid residues.In certain embodiments, R² For OH or NH₂。

In certain embodiments, X includes the sequence of Formula X a.

In the specific embodiment of formula (I), X includes the sequence of Formulas I a：

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Ia)

Wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn, Dap, Dab, D- The chloro- acetic acid of Dap, D-Dab, D-Asp, D-Glu, D-Lys, Sec, 2- chloromethyl benzoic acid, mercaptopropionic acid, mercaptobutyric acid, 2-, 3- The chloro- butyric acid of chloro- propionic acid, 4-, the chloro- isobutyric acids of 3-, Abu, β-azido-Ala-OH, propargylglycine, 2- (3 '-cyclobutenyl) Glycine, 2- allylglycines, 2- (3 '-cyclobutenyl) glycine, 2- (4 '-pentenyl) glycine, 2- (5 '-hexenyl) are sweet Propylhomoserin is not present；

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D- Leu、D-Thr、D-Ser、α-MeOrn、α-MeSer、CitDap、Dab、Dap(Ac)、Gly、Lys、Asn、N-Me-Gln、N-Me- Arg, Orn or Gln,

X6 is Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn or D-Phe；

X8 is Val, Gln, Glu or Lys；

X9 be Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Asp, Leu, Val, Phe, Ser, Sec, Abu, β-azido-Ala-OH, propargylglycine, 2- 2- allylglycines, 2- (3 '-cyclobutenyl) glycine, 2- (4 '-pentenyl) glycine or 2- (5 '-hexenyl) glycine；

X10 is Tyr, Phe, Phe (3,4-F₂), Phe (3,4-Cl₂), F (3-Me), Phe [4- (2- amino ethoxies)], Phe [4- (2- (acetyl-amino ethoxy)], Phe (4-Br), Phe (4-CONH₂)、Phe(4-Cl)、Phe(4-CN)、Phe(4- Guanidine radicals), Phe (4-Me), Phe (4-NH₂)、Phe(4-N₃), Phe (4-OMe), Phe (4-OBzl) or Tyr；

X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe₂) 5- hydroxyls-Trp, Phe (3,4-Cl₂) or Tyr (3-t-Bu)

X12 be His, Phe, Arg, N-Me-His or Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl-Ala, Tertiary butyl-Gly, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α - MeLys、α-MeLys(Ac)、α-Me-Leu、α-MeOrn、α-MeSer、α-MeVal、Cha、Cit、Cpa、(D)Asn、Glu、 HArg or Lys；

X13 be Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, β hAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn or Gln；

X14 is Phe, Tyr, β hPhe, Asn, Arg, Qln, Lys (Ac), His；Dap (Ac), Dab (Ac) or Asp；

X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present.

In the specific embodiment of Ia：X5 be Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib or D-Sarc；X10 is Tyr or Phe；X11 is Trp, 1- Nal or 2-Nal；X12 is His, Phe, Arg, N-Me-His or Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl- Ala or tertiary butyl-Gly；X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, β hAla or Aib；X14 is Phe, Tyr Or β hPhe；X15 is Gly, Ser, Thr, Gln, Ala or Sarc；X16 be Asp, Glu, Ala, AEA, AEP, β hAla, Gaba or It is not present；And X17 is Leu, Lys, Arg or is not present.

In a particular embodiment, X4 is existing.

In certain embodiments, inhibitor peptides are cyclisation.

In certain embodiments, inhibitor peptides are linear or are not cyclisation.

In certain embodiments, inhibitor peptides are to be cyclized or contain between X4 and X9 intramolecular bond.

In certain embodiments of Formulas I, X includes the sequence of Formulas I b：

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Ib),

Wherein：

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D- The chloro- acetic acid of Dab, D-Asp, D-Glu, D-Lys, Sec, 2- chloromethyl benzoic acid, mercaptopropionic acid, mercaptobutyric acid, 2-, 3- chloro- third Acid, the chloro- butyric acid of 4-, the chloro- isobutyric acids of 3-, Abu, β-azido-Ala-OH, propargylglycine, 2- (3 '-cyclobutenyl) sweet ammonia Acid, 2-2- allylglycines, 2- (3 '-cyclobutenyl) glycine, 2- (4 '-pentenyl) glycine, 2- (5 '-hexenyl) sweet ammonia Acid is not present；

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D- Leu、D-Thr、D-Ser、α-MeOrn、α-MeSer、CitDap、Dab、Dap(Ac)、Gly、Lys、Asn、N-Me-Gln、N-Me- Arg, Orn or Gln；

X6 is Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn or D-Phe；

X8 is Val, Gln, Glu or Lys；

X9 be Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Asp, Sec, Abu, β-azido-Ala-OH, propargylglycine, 2- allylglycines, 2- (3 '-cyclobutenyl) glycine, 2- (4 '-pentenyl) glycine or 2- (5 '-hexenyl) glycine；

X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe₂) 5- hydroxyls-Trp, Phe (3,4-Cl₂)、Tyr(3-t-Bu)；

X12 be His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl-Ala, Tertiary butyl-Gly4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α - MeLys、α-MeLys(Ac)、α-Me-Leu、α-MeOrn、α-MeSer、α-MeVal、Cha、Cit、Cpa、(D)Asn、Glu、 HArg or Lys；

X13 be Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, β hAlaAib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, bArg, Lys, Asn, Orn or Gln；

X14 is Phe, Tyr or β hPhe, Asn, Arg, Qln, Lys (Ac), His；Dap (Ac), Dab (Ac) or Asp；

X15 is Gly, Ser, Thr, Gln, Ala or Sarc, β-Ala, Glu, Arg or Asn；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present.

In the specific embodiment of Ib：X5 be Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib or D-Sarc；X10 is Tyr or Phe；X11 is Trp, 1- Nal or 2-Nal；X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl- Ala or tertiary butyl-Gly；X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, β hAla or Aib；X14 is Phe, Tyr Or β hPhe；X15 is Gly, Ser, Thr, Gln, Ala or Sarc；X16 be Asp, Glu, Ala, AEA, AEP, β hAla, Gaba or It is not present；And X17 is Leu, Lys, Arg or is not present.

In a particular embodiment, X4 is existing.

In certain embodiments, inhibitor peptides are cyclisation.

In certain embodiments, inhibitor peptides are linear or are not cyclisation.

In certain embodiments of Formulas I, X includes the sequence of Formulas I c：

X1-X2-X3-X4-X5-X6-W-X8-X9-Y-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20

(Ic)

Wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn, Dap, Dab, D- The chloro- acetic acid of Dap, D-Dab, D-Asp, D-Glu, D-Lys, Sec, 2- chloromethyl benzoic acid, mercaptopropionic acid, mercaptobutyric acid, 2-, 3- The chloro- butyric acid of chloro- propionic acid, 4-, the chloro- isobutyric acids of 3-, Abu, β-azido-Ala-OH, propargylglycine, the sweet ammonia of 2- allyls Acid, 2- (3 '-cyclobutenyl) glycine, 2- (4 '-pentenyl) glycine, 2- (5 '-hexenyl) glycine are not present；

X6 is Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn or D-Phe；

X8 is Val, Gln, Glu or Lys；

X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe₂), 5- hydroxyls-Trp, Phe (3,4-Cl₂) or Tyr (3-t- Bu)；

X12 be His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl-Ala, Tertiary butyl-Gly；4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α - MeLys、α-MeLys(Ac)、α-Me-Leu、α-MeOrn、α-MeSer、α-MeVal、Cha、Cit、Cpa、(D)Asn、Glu、 HArg or Lys；

X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, β hAla or Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn or Gln；

X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present.

In the specific embodiment of Ic, X5 Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib or D-Sarc；X11 is Trp, 1-Nal or 2-Nal；X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl-Ala or tertiary butyl-Gly； X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, β hAla or Aib；X14 is Phe, Tyr or β hPhe；X15 is Gly, Ser, Thr, Gln, Ala or Sarc；X16 is Asp, Glu, Ala, AEA, AEP, β hAla, Gaba or is not present；And X17 For Leu, Lys, Arg or it is not present.

In a particular embodiment, X4 is existing.

In certain embodiments, inhibitor peptides are cyclisation.

In certain embodiments, inhibitor peptides are linear or are not cyclisation.

In certain embodiments of Formulas I, X includes the sequence of Formulas I d：

X1-X2-X3-C-X5-X6-W-X8-C-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20

(Id)

Wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X6 is Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn or D-Phe；

X8 is Val, Gln, Glu or Lys；

X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe₂), 5- hydroxyls-Trp, Phe (3,4-Cl₂)、Tyr(3-t- Bu)；

X12 be His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl-Ala, Tertiary butyl-Gly, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α - MeLys、α-MeLys(Ac)、α-Me-Leu、α-MeOrn、α-MeSer、α-MeVal、Cha、Cit、Cpa、(D)Asn、Glu、 HArg or Lys；

X14 is Phe, Tyr, β hPhe, Asn, Arg, Qln, Lys (Ac), His, Dap (Ac), Dab (Ac) or Asp；

X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present,

Wherein X4 is connected with X9 optionally by the disulphide bridges of intramolecular.

In certain embodiments of Id：X5 be Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib or D-Sarc；X10 is Tyr or Phe；X11 is Trp, 1- Nal or 2-Nal；X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl- Ala or tertiary butyl-Gly；X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, β hAla or Aib；X14 is Phe, Tyr Or β hPhe；X15 is Gly, Ser, Thr, Gln, Ala or Sarc；X16 be Asp, Glu, Ala, AEA, AEP, β hAla, Gaba or It is not present；And X17 is Leu, Lys, Arg or is not present.

In certain embodiments of Formulas I, X includes the sequence of Formulas I e：

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20

(Ie) wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X4 is Pen, hCys, D-Pen, D-Cys or D-hCys；

X6 is Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn or D-Phe；

X8 is Val, Gln, Glu or Lys；

X9 is Pen, hCys, D-Pen, D-Cys, D-hCys；

X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present,

Wherein X4 and X9 connects optionally by intramolecular disulfide bridging.

In certain embodiments of Ie：X5 be Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib or D-Sarc；X10 is Tyr or Phe；X11 is Trp, 1- Nal or 2-Nal；X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl- Ala or tertiary butyl-Gly；X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, β hAla or Aib；X14 is Phe, Tyr Or β hPhe；X15 is Gly, Ser, Thr, Gln, Ala or Sarc；X16 be Asp, Glu, Ala, AEA, AEP, β hAla, Gaba or It is not present；And X17 is Leu, Lys, Arg or is not present.

In a particular embodiment, X4 is existing.

In certain embodiments, inhibitor peptides are cyclisation.

In certain embodiments, inhibitor peptides are linear or are not cyclisation.

In a particular embodiment, X4 and X9 is Pen.

In certain embodiments of Formulas I, X includes the sequence of Formulas I f：

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20

(If)

Wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X4 is Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys or Asp；

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D- Leu、D-Thr、D-Ser、α-MeOrn、α-MeSer、Cit、Dap、Dab、Dap(Ac)、Gly、Lys、Asn、N-Me-Gln、N- Me-Arg, Orn or Gln；

X6 is Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn or D-Phe；

X8 is Val, Gln, Glu or Lys；

X9 is Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys or Asp；

X10 be Tyr, Phe, Phe (3,4-F2), Phe (3,4-Cl2), F (3-Me), Phe [4- (2- amino ethoxies)], Phe [4- (2- (acetyl-amino ethoxy)], Phe (4-Br), Phe (4-CONH2), Phe (4-Cl), Phe (4-CN), Phe (4- Guanidine radicals), Phe (4-Me), Phe (4-NH2), Phe (4-N₃), Phe (4-OMe), Phe (4-OBzl) or Tyr；

X12 be His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl-Ala or Tertiary butyl-Gly, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α - MeLys、α-MeLys(Ac)、α-Me-Leu、α-MeOrn、α-MeSer、α-MeVal、Cha、Cit、Cpa、(D)Asn、Glu、 HArg or Lys；

X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present,

Wherein X4 and X9 are cyclized optionally by intramolecular bond.

In certain embodiments of If：X5 be Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib or D-Sarc；X6 be Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn or D-Phe；X8 is Val, Gln, Glu or Lys；X9 be Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys or Asp；X10 is Tyr or Phe；X11 is Trp, 1-Nal or 2-Nal；X12 be His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl-Ala or tertiary butyl-Gly；X13 be Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, β hAla or Aib；X14 is Phe, Tyr or β hPhe；X15 be Gly, Ser, Thr, Gln, Ala or Sarc；X16 is Asp, Glu, Ala, AEA, AEP, β hAla, Gaba or is not present；And X17 be Leu, Lys, Arg or It is not present.

In certain embodiments, intramolecular bond is lactam bond.

In certain embodiments of Formulas I, X includes the sequence of Formulas I g：

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20

(Ig)

Wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X4 is β-azido-Ala-OH or propargylglycine；

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D- Leu、D-Thr、D-Ser、α-MeOrn、α-MeSer、Cit、Dap、Dab、Dap(Ac)、Gly、Lys、Asn、N-MeGln、N- MeArg, Orn or Gln；

X6 is Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn or D-Phe；

X8 is Val, Gln, Glu or Lys；

X9 is β-azido-Ala-OH or propargylglycine；

X15 is Gly, Ser, Thr, Gln, Ala or Sarc, β-Ala, Glu, Arg or Asn；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present,

Wherein X4 and X9 is cyclized optionally by the triazole ring of intramolecular.

In the specific embodiment of Ig：X5 be Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib or D-Sarc；X6 be Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn or D-Phe；X8 is Val, Gln, Glu or Lys；X9 is β-azido-Ala-OH or propargylglycine；X10 For Tyr or Phe；X11 is Trp, 1-Nal or 2-Nal；X12 be His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl-Ala or tertiary butyl-Gly；X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, β HAla or Aib；X14 is Phe, Tyr or β hPhe；X15 is Gly, Ser, Thr, Gln, Ala or Sarc；X16 be Asp, Glu, Ala, AEA, AEP, β hAla, Gaba are not present；And X17 is Leu, Lys, Arg or is not present.

In certain embodiments of Formulas I, X includes the sequence of Formulas I h：

X1-X2-X3-C-X5-X6-W-X8-C-Y-X11-H-X13-F-X15-X16-X17-X18-X19-X20

(Ih)

Wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X4 be 2- allylglycines, 2- (3 '-cyclobutenyl) glycine, 2- (4 '-pentenyl) glycine or 2- (5 '-oneself Alkenyl) glycine；

X5 is Ala, Arg, Sarc, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N- MeGln, N-MeArg, Orn or Gln；

X6 is Asp, Thr or Asn；

X8 is Val, Gln or Glu；

X9 be 2- allylglycines, 2- (3 '-cyclobutenyl) glycine, 2- (4 '-pentenyl) glycine or 2- (5 '-oneself Alkenyl) glycine；

X13 be Thr, Sarc, Glu, Phe, Arg, Leu, Lys, β hAla, Val, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn or Gln；

X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present,

Wherein X4 and X9 is optionally cyclized via the cultural care of intramolecular (ring closing methasis) To generate corresponding alkene.

In the specific embodiment of Ih：X5 is Ala, Arg or Sarc；X6 is Asp, Thr or Asn；X11 is Trp, 1- Nal or 2-Nal；X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, β hAla, Val or Aib；X15 be Gly, Ser, Thr, Gln, Ala or Sarc；X16 is Asp, Glu, Ala, AEA, AEP, β hAla, Gaba or is not present；And X17 be Leu, Lys, Arg is not present.

In certain embodiments of Formulas I, X includes the sequence of Formulas I i：

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Ii),

Wherein：

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X4 be Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, 2- chloromethyl benzoic acid, mercaptopropionic acid, mercaptobutyric acid, The chloro- acetic acid of 2-, the chloro- propionic acid of 3-, the chloro- butyric acid of 4- or the chloro- isobutyric acids of 3-；

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D- Leu, D-Thr, D-Ser, D-Aib or D-Sarc, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln；

X6 is Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn or D-Phe；

X8 is Val, Gln, Glu or Lys；

X9 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys or Abu；

X12 be His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl-Ala, Tertiary butyl-Gly, 4- amino -4- carboxyls-oxinane, AchcAcpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α - MeLys、α-MeLys(Ac)、α-Me-Leu、α-MeOrn、α-MeSer、α-MeVal、Cha、Cit、Cpa、(D)Asn、Glu、 HArg or Lys；

X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present,

Wherein X4 and X9 is optionally cyclized via intramolecular thioether bond.

In the specific embodiment of Ii：X5 be Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib or D-Sarc；X6 be Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn or D-Phe；X10 is Tyr or Phe；X11 is Trp, 1-Nal or 2-Nal；X12 is His, Phe, Arg, N-Me- His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl-Ala or tertiary butyl-Gly；X13 be Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, β hAla or Aib；X14 is Phe, Tyr or β hPhe；X15 be Gly, Ser, Thr, Gln, Ala or Sarc；X16 is Asp, Glu, Ala, AEA, AEP, β hAla, Gaba or is not present；And X17 is Leu, Lys, Arg or does not deposit .

In certain embodiments of Formulas I, X includes the sequence of Formulas I j：

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Ij),

Wherein：

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X4 is Sec, 2- chloromethyl benzoic acid, the chloro- propionic acid of 3-, the chloro- butyric acid of 4-, the chloro- isobutyric acids of 3- or Abu；

X6 is Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn or D-Phe；

X8 is Val, Gln, Glu or Lys；

X9 is Sec or Abu；

X10 is Tyr, Phe, Phe (3,4-F₂), Phe (3,4-Cl₂), F (3-Me), Phe [4- (2- amino ethoxies)], Phe [4- (2- amino ethoxies), Phe [4- (2- (acetyl-amino ethoxy)], Phe (4-Br), Phe (4-CONH₂)、Phe (4-Cl), Phe (4-CN), Phe (4- guanidine radicals), Phe (4-Me), Phe (4-NH₂)、Phe(4-N₃)、Phe(4-OMe)、Phe(4- ) or Tyr OBzl；

X12 be His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl-Ala, Tertiary butyl-Gly, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D) Asn, Glu, hArg or Lys；

X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present,

Sulphur selenium keys or two selenium keys cyclisation of the wherein X4 and X9 optionally through intramolecular.

In the specific embodiment of Ij：X5 be Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib or D-Sarc；X10 is Tyr or Phe；X11 is Trp, 1- Nal or 2-Nal；X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl- Ala or tertiary butyl-Gly；X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, β hAla or Aib；X14 is Phe, Tyr Or β hPhe；X15 is Gly, Ser, Thr, Gln, Ala or Sarc；X16 be Asp, Glu, Ala, AEA, AEP, β hAla, Gaba or It is not present；And X17 is Leu, Lys, Arg or is not present.

In certain embodiments of Formulas I, X includes the sequence of Formulas I k：

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Ik),

Wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn, Dap, Dab, D- Dap, D-Dab, D-Asp, D-Glu, D-Lys are not present；

X6 is Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn or D-Phe；

X8 is Val, Gln, Glu or Lys；

X9 be Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Asp, Leu, Val, Phe or Ser；

X12 is His, Phe, Arg, N-Me-His, Val, D-His, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary fourth Base-Ala, tertiary butyl-Gly, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly、α-MeLys、α-MeLys(Ac)、α-Me-Leu、α-MeOrn、α-MeSer、α-MeVal、Cha、Cit、Cpa、(D)Asn、 Glu, hArg or Lys；

X14 is Phe, Tyr, β hPhe, Asn, Arg, Qln, Lys (Ac), His；Dap (Ac), Dab (Ac) or Asp or not In the presence of；

X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn or is not present；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present.

In the specific embodiment of Ik：X5 be Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib or D-Sarc；X10 is Tyr or Phe；X11 is Trp, 1- Nal or 2-Nal；X12 is His, Phe, Arg, N-Me-His, Val, D-His, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, uncle Butyl-Ala or tertiary butyl-Gly；X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, β hAla, Aib or is not present； X14 is Phe, Tyr, β hPhe or is not present；X15 is Gly, Ser, Thr, Gln, Ala, Sarc or is not present；X16 be Asp, Glu, Ala, AEA, AEP, β hAla, Gaba, Leu are not present；And X17 is Leu, Lys, Arg or is not present.

In certain embodiments of Formulas I, X includes the sequence of Formulas I l or is made from it：

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Il),

Wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X5 be Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln；

X6 is Asp, Thr, Asn or Phe；

X8 is Val, Gln, Glu or Lys；

X13 be Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, β hAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn or Gln are not present；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present.

In the specific embodiment of Il：X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib or Sarc；X10 is Tyr or Phe；X11 is Trp, 1-Nal or 2-Nal；X12 be His, Phe, Arg, N-Me-His, Val, D-His, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl-Ala or tertiary butyl-Gly；X13 be Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Val, β hAla, Aib are not present；X14 is Phe, Tyr, β hPhe or is not present；X15 be Gly, Ser, Thr, Gln, Ala, Sarc is not present；X16 is Asp, Glu, Ala, AEA, AEP, β hAla, Gaba, Leu or is not present；And X17 be Leu, Lys, Arg are not present.

In certain embodiments, X13 Thr, Sarc, Glu, Phe, Arg, Leu, Lys, β hAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn or Gln.In certain embodiments, X13 Thr, Sarc, Glu, Phe, Arg, Leu, Lys, β hAla or Aib.

In certain embodiments, X14 Phe, Tyr, β hPhe, Asn, Arg, Qln, Lys (Ac), His；Dap(Ac)、 Dab (Ac) or Asp.In certain embodiments, X14 Phe, Tyr or β hPhe.

In certain embodiments, X15 Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn. In certain embodiments, X15 Gly, Ser, Thr, Gln, Ala or Sarc.

In certain embodiments, X12 is alpha amino acid, for example, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Aib, α-MeGly (diethyl), α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α- MeVal。

In certain embodiments, X13 is existing.

In certain embodiments, X13 and X14 is existing.

In certain embodiments, X13, X14 and X15 are existing.

In a particular embodiment, X4 is existing.

In certain embodiments, inhibitor peptides are cyclisation.

In certain embodiments, inhibitor peptides are linear or are not cyclisation.

In certain embodiments of the inhibitor peptides of Formulas I, X includes the sequence of Formulas I m or is made from it：

X1-X2-X3-X4-X5-X6-W-X8-X9-Y-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Im),

Wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X6 is Asp, Thr, Asn or Phe；

X8 is Val, Gln, Glu or Lys；

X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe₂)；5- hydroxyls-Trp, Phe (3,4-Cl₂) or Tyr (3-t- Bu)；

X13 be Thr, Sarc, Glu, Phe, Arg, Leu, Lys, β hAla, Val, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn or Gln are not present；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present.

In certain embodiments of Im：X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib or Sarc；X11 is Trp, 1-Nal or 2-Nal；X12 is His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, uncle Butyl-Ala or tertiary butyl-Gly；X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, β hAla, Val, Aib or is not present； X14 is Phe, Tyr, β hPhe or is not present；X15 is Gly, Ser, Thr, Gln, Ala, Sarc or is not present；X16 be Asp, Glu, Ala, AEA, AEP, β hAla, Gaba are not present；And X17 is Leu, Lys, Arg or is not present.

In certain embodiments, X13 Thr, Sarc, Glu, Phe, Arg, Leu, Lys, β hAla or Aib.Certain In embodiment, X13 Thr, Sarc, Glu, Phe, Arg, Leu, Lys, β hAla, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn or Gln.

In certain embodiments, X15 Gly, Ser, Thr, Gln, Ala or Sarc, β-Ala, Glu, Arg or Asn. In certain embodiments, X15 Gly, Ser, Thr, Gln, Ala or Sarc.

In certain embodiments, X13 is existing.

In certain embodiments, X13 and X14 is existing.

In certain embodiments, X13, X14 and X15 are existing.

In a particular embodiment, X14 is existing.

In certain embodiments, inhibitor peptides are cyclisation.

In certain embodiments, inhibitor peptides are linear or are not cyclisation.

In certain embodiments of the inhibitor peptides of Formulas I, X includes the sequence of Formulas I n or is made from it：

X1-X2-X3-C-X5-X6-W-X8-C-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (In)

Wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X6 is Asp, Thr, Asn or Phe；

X8 is Val, Gln, Glu or Lys；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present,

Wherein X4 Cys and X9 Cys is connected optionally by disulphide bridges.

In certain embodiments of In：X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, α- MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln；X10 is Tyr, Phe, Phe (3,4-F₂), Phe (3,4-Cl₂), F (3-Me), Phe [4- (2- amino ethoxies)], Phe [4- (2- (acetyl- Amino ethoxy)], Phe (4-Br), Phe (4-CONH₂), Phe (4-Cl), Phe (4-CN), Phe (4- guanidine radicals), Phe (4- Me)、Phe(4-NH₂)、Phe(4-N₃), Phe (4-OMe), Phe (4-OBzl) or Tyr；X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe₂), 5- hydroxyls-Trp, Phe (3,4-Cl₂) or Tyr (3-t-Bu)；X12 be His, Phe, Arg, N-Me-His, Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl-Ala or tertiary butyl-Gly, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, Cha, Cit, Cpa, (D) Asn, Glu, hArg or Lys；X13 be Thr, Sarc, Glu, Phe, Arg, Leu, Lys, β hAla, Val, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn or Gln or not In the presence of；X14 is Phe, Tyr, β hPhe, Asn, Arg, Qln, Lys (Ac), His；Dap (Ac), Dab (Ac) or Asp are not deposited ；X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn or is not present；X16 be Asp, Glu, Ala, AEA, AEP, β hAla, Gaba are not present；And X17 is Leu, Lys, Arg or is not present.

In certain embodiments, X12 is alpha amino acid, for example, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α- MeVal。

In certain embodiments, X13 is existing.

In certain embodiments, X13 and X14 is existing.

In certain embodiments, X13, X14 and X15 are existing.

In certain embodiments of the inhibitor peptides of Formulas I, X includes the sequence of Formulas I o or is made from it：

X1-X2-X3-C-X5-X6-W-X8-C-Y-X11-H-X13-X14-X15-X16-X17-X18-X19-X20(Io)

Wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X6 is Asp, Thr, Asn or Phe；

X8 is Val, Gln, Glu or Lys；

X14 is Phe, Tyr, Asn, Arg, Qln, Lys (Ac), His；Dap (Ac), Dab (Ac) or Asp are not present；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present,

Wherein X4 Cys and X9 Cys is connected optionally by disulphide bridges.

In certain embodiments of Io：X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, α- MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn or Gln；X11 is Trp, 1-Nal, 2-Nal, Phe (3,4-OMe₂), 5- hydroxyls-Trp, Phe (3,4-Cl₂) or Tyr (3-t-Bu)；X13 be Thr, Sarc、Glu、Phe、Arg、Leu、Lys、βhAla、Val、Aib、Lys(Ac)、Cit、Asp、Dab、Dap、Glu、hArg、Lys、 Asn, Orn, Gln are not present；X14 is Phe, Tyr, Asn, Arg, Qln, Lys (Ac), His；Dap(Ac)、Dab(Ac)、Asp Or it is not present；X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg or Asn or is not present；X16 be Asp, Glu, Glu, Ala, AEA, AEP, β hAla, Gaba are not present；And X17 is Leu, Lys, Arg or is not present.

In certain embodiments, X14 Phe, Tyr, Asn, Arg, Qln, Lys (Ac), His；Dap(Ac)、Dab(Ac) Or Asp.In certain embodiments, X14 is Phe or Tyr.

In certain embodiments, X13 is existing.

In certain embodiments, X13 and X14 is existing.

In certain embodiments, X13, X14 and X15 are existing.

In certain embodiments of the inhibitor peptides of Formulas I, X includes the sequence of Formulas I p or is made from it：

X1-X2-X3-C-X5-X6-W-X8-C-Y-X11-H-X13-F-X15-X16-X17-X18-X19-X20(Ip)

Wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X6 is Asp, Thr or Asn；

X8 is Val, Gln or Glu；

X13 be Thr, Sarc, Glu, Phe, Arg, Leu, Lys, β hAla, Val, Aib, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, Gln are not present；

X15 is Gly, Ser, Thr, Gln, Ala, Sarc, β-Ala, Glu, Arg, Asn or is not present；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present,

Wherein X4 Cys and X9 Cys is connected optionally by disulphide bridges.

In certain embodiments of Ip：X5 is Ala, Arg or Sarc；X11 is Trp, 1-Nal or 2-Nal；X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, β hAla, Val, Aib are not present；X15 be Gly, Ser, Thr, Gln, Ala, Sarc is not present；X16 is Asp, Glu, Ala, AEA, AEP, β hAla, Gaba or is not present；And X17 is Leu, Lys, Arg Or it is not present.

In certain embodiments, X13 is existing.

In certain embodiments, X13 and X14 is existing.

In certain embodiments, X13, X14 and X15 are existing.

In certain embodiments of the inhibitor peptides of Formulas I, X includes the sequence of Formulas I q or is made from it：

X1-X2-X3-C-X5-X6-W-X8-C-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Iq),

Wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X5 is Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D- Leu、D-Thr、D-Ser、D-Aib、D-Sarc、α-MeOrn、α-MeSer、Cit、Dap、Dab、Dap(Ac)、Gly、Lys、Asn、 N-MeGln, N-MeArg, Orn or Gln；

X6 is Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn or D-Phe；

X8 is Val, Gln, Glu or Lys；

X12 is His, Phe, Arg, N-Me-His, Val or D-His, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary fourth Base-Ala, tertiary butyl-Gly, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly、α-MeLys、α-MeLys(Ac)、α-Me-Leu、α-MeOrn、α-MeSer、α-MeVal、Cha、Cit、Cpa、(D)Asn、 Glu, hArg or Lys；

X14 is Phe, Tyr, β hPhe, Asn, Arg, Qln, Lys (Ac), His；Dap (Ac), Dab (Ac), Asp are not deposited ；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present,

Wherein X4 Cys and X9 Cys is optionally connected.

In certain embodiments of Iq：X5 be Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib or D-Sarc；X10 is Tyr or Phe；X11 is Trp, 1- Nal or 2-Nal；X12 is His, Phe, Arg, N-Me-His, Val or D-His, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, uncle Butyl-Ala or tertiary butyl-Gly；X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, β hAla, Val, Aib or is not present； X14 is Phe, Tyr, β hPhe or is not present；X15 is Gly, Ser, Thr, Gln, Ala, Sarc or is not present；X16 be Asp, Glu, Ala, AEA, AEP, β hAla, Gaba, Leu are not present；And X17 is Leu, Lys, Arg or is not present.

In certain embodiments, X13 is existing.

In certain embodiments, X13 and X14 is existing.

In certain embodiments, X13, X14 and X15 are existing.

In certain embodiments, Iq includes the sequence of Formulas I q ' or is made from it：

X1-X2-X3-C-X5-X6-W-X8-C-X10-X11-X12-X13-X14-X15 (Iq '),

Wherein X1-X14 has the definition provided by Iq, and

Wherein X4 Cys and X9 Cys is optionally connected.

In certain embodiments of Iq '：X5 be Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D-Arg, D-Glu, D-Phe, D-Leu, D-Thr, D-Ser, D-Aib or D-Sarc；X10 is Tyr or Phe；X11 is Trp, 1- Nal or 2-Nal；X12 is His, Phe, Arg, N-Me-His, Val or D-His, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, uncle Butyl-Ala or tertiary butyl-Gly；X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, β hAla, Val, Aib or is not present； X14 is Phe, Tyr, β hPhe or is not present；X15 is Gly, Ser, Thr, Gln, Ala, Sarc or is not present；X16 be Asp, Glu, Ala, AEA, AEP, β hAla, Gaba, Leu are not present；And X17 is Leu, Lys, Arg or is not present.

In certain embodiments, X15 Gly, Ser, Thr, Gln, Ala or Sarc, β-Ala, Glu, Arg or Asn. In certain embodiments, X14 Phe, Tyr or β hPhe.

In certain embodiments, X13 is existing.

In certain embodiments, X13 and X14 is existing.

In certain embodiments, X13, X14 and X15 are existing.

In certain embodiments of the inhibitor peptides of Formulas I, X includes the sequence of Formulas I r or is made from it：

X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19- X20(Ir)

Wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X4 is Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Met, Glu, Asp, Lys, Orn, Dap, Dab, D- The chloro- acetic acid of Dap, D-Dab, D-Asp, D-Glu, D-Lys, Sec, 2- chloromethyl benzoic acid, mercaptopropionic acid, mercaptobutyric acid, 2-, 3- The chloro- butyric acid of chloro- propionic acid, 4-, the chloro- isobutyric acids of 3-, Abu, β-azido-Ala-OH, propargylglycine, 2- (3 '-cyclobutenyl) Glycine, 2- allylglycines, 2- (3 '-cyclobutenyl) glycine, 2- (4 '-pentenyl) glycine, 2- (5 '-hexenyl) are sweet Propylhomoserin, Abu are not present；

X5 is arbitrary amino acid；

X6 is arbitrary amino acid；

X7 is Trp, Glu, Gly, Ile, Asn, Pro, Arg, Thr or OctGly or arbitrary aforementioned corresponding Alpha-Methyl ammonia Base acid form；

X8 is arbitrary amino acid；

X9 be Cys, Pen, hCys, D-Pen, D-Cys, D-hCys, Glu, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu, D-Lys, Asp, Leu, Val, Phe or Ser, Sec, Abu, β-azido-Ala-OH, propargylglycine, 2-2- allylglycines, 2- (3 '-cyclobutenyl) glycine, 2- (4 '-pentenyl) glycine, Ala, hCys, Abu, Met, MeCys, (D) Tyr or 2- (5 '-hexenyl) glycine；

X10 is Tyr, Phe (4-OMe), 1-Nal, 2-Nal, Aic, α-MePhe, Bip, (D) Cys, Cha, DMT, (D) Tyr, Glu, His, hPhe (3,4- dimethoxy), hTyr, N-Me-Tyr, Trp, Phe (4-CONH₂), Phe (4- phenoxy groups), Thr、Tic、Tyr(3-tBu)、Phe(4-tBu)、Phe(4-CN)、Phe(4-Br)、Phe(4-NH₂), Phe (4-F), Phe (3, 5-F₂)、Phe(4-CH₂CO₂H), Phe (5-F), Phe (3,4-Cl₂)、Phe(4-CF₃), Bip, Cha, 4- pyriylalanine, β hTyr、OctGly、Phe(4-N₃), Phe (4-Br), Phe [4- (2- amino ethoxies)] or Phe, Phe analog, Tyr it is similar Object or arbitrary aforementioned corresponding Alpha-Methyl amino acid form；

X11 is 2-Nal, 1-Nal, 2,4- dimethyl Phe, Bip, Phe (3,4-Cl₂), Phe (3,4-F₂)、Phe(4- CO₂H), β hPhe (4-F), α-Me-Trp, 4- phenylcyclohexyls, Phe (4-CF₃), Phe (3,4-OMe₂)、α-MePhe、β HNal, β hPhe, β hTyr, β hTrp, Nva (5- phenyl), Phe, His, hPhe, Tic, Tqa, Trp, Tyr, Phe (4-OMe), Phe (4-Me), Trp (2,5,7- tri--tertiary butyl), Phe (4-O allyls), Tyr (3-tBu), Phe (4-tBu), Phe (4- guanidines Base, Phe (4-OBzl), Octgly, Glu (Bzl), 4- phenylbenzyls alanine, Phe [4- (2- amino ethoxies)], 5- hydroxyls- The chloro- Trp, N-MeTrp of Trp, 6-, 1,2,3,4- tetrahydrochysenes-norharmane, Phe (4-CONH₂), Phe (3,4- dimethoxy), Phe (2,3-Cl₂), Phe (2,3-F₂), Phe (4-F), 4- phenylcyclohexyls alanine or Bip or arbitrary aforementioned corresponding α- Methylamino acid form；

X12 be His, Phe, Arg, N-Me-His or Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary butyl-Ala, α-MeLys、D-Ala、(D)Asn、(D)Asp、(D)Leu、(D)Phe、(D)Tyr、Aib、α-MeLeu、α-MeOrn、β-Aib、β- Ala, β hAla, β hArg, β hLeu, β hVal, β-spiral shell-pip, Glu, hArg, Ile, Lys, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Ser, Thr, Tle or tertiary butyl-Gly, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α- MeVal, Cha, Cit, Cpa, (D) Asn, Glu, hArg or Lys or arbitrary aforementioned corresponding Alpha-Methyl amino acid form；

X13 be Thr, Sarc, Glu, Phe, Arg, Leu, Asn, Cit, Lys, Arg, Orn, Val, β hAla, Lys (Ac), (D) Asn, (D) Leu, (D) Phe, (D) Thr, Ala, α-MeLeu, Aib, β-Ala, β-Glu, β hLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, hLeu, Asn, Ogl, Pro, Gln, Ser, β-spiral shell-pip, Thr, Tba, Tle Or Aib or arbitrary aforementioned corresponding Alpha-Methyl amino acid form；

X14 be Phe, Tyr, Glu, Gly, His, Lys, Leu, Met, Asn, Lys (Ac), Dap (Ac), Asp, Pro, Gln, Arg, Ser, Thr, Tic or β hPhe or arbitrary aforementioned corresponding Alpha-Methyl amino acid form；

X15 be Gly, Ser, Thr, Gln, Ala, (D) Ala, (D) Asn, (D) Asp, (D) Leu, (D) Phe, (D) Thr, Aea, Asp, Asn, Glu, Phe, Gly, Lys, Leu, Pro, Arg, β-Ala or Sarc or arbitrary aforementioned corresponding Alpha-Methyl ammonia Base acid form；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present.

In a particular embodiment, the peptide is cyclized via X4 and X9.

In a particular embodiment, X3 Glu, D-Glu, Arg, (D) Arg, Phe, (D) Phe, 2-Nal, Thr, Leu, (D)Gln。

In certain embodiments of Ir：X11 is 2-Nal, 1-Nal, 2,4- dimethyl Phe, Bip, Phe (3,4-Cl₂)、 Phe (3,4-F₂)、Phe(4-CO₂H), β hPhe (4-F), α-Me-Trp, 4- phenylcyclohexyls, Phe (4-CF₃)、α-MePhe、β HNal, β hPhe, β hTyr, β hTrp, Nva (5- phenyl), Phe, His, hPhe, Tic, Tqa, Trp, Tyr, Phe (4-OMe), Phe (4-Me), Trp (2,5,7- tri--tertiary butyl), Phe (4-O allyls), Tyr (3-tBu), Phe (4-tBu), Phe (4- guanidines Base, Phe (4-OBzl), Octgly, Glu (Bzl), 4- phenylbenzyls alanine, Phe [4- (2- amino ethoxies)], 5- hydroxyls- The chloro- Trp, N-MeTrp of Trp, 6-, 1,2,3,4- tetrahydrochysenes-norharmane, Phe (4-CONH₂), Phe (3,4- dimethoxy), Phe (2,3-Cl₂), Phe (2,3-F₂), Phe (4-F), 4- phenylcyclohexyls alanine or Bip or arbitrary aforementioned corresponding α- Methylamino acid form；X12 is His, Phe, Arg, N-Me-His or Val, Cav, Cpa, Leu, Cit, hLeu, 3-Pal, tertiary fourth Base-Ala, α-MeLys, D-Ala, (D) Asn, (D) Asp, (D) Leu, (D) Phe, (D) Tyr, Aib, α-MeLeu, α-MeOrn, β-Aib, β-Ala, β hAla, β hArg, β hLeu, β hVal, β-spiral shell-pip, Glu, hArg, Ile, Lys, N-MeLeu, N- MeArg, Ogl, Orn, Pro, Gln, Ser, Thr, Tle or tertiary butyl-Gly or arbitrary aforementioned corresponding Alpha-Methyl amino acid shape Formula；X13 be Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Arg, Orn, Val, β hAla, Lys (Ac), (D) Asn, (D) Leu, (D) Phe, (D) Thr, Ala, α-MeLeu, Aib, β-Ala, β-Glu, β hLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, hLeu, Asn, Ogl, Pro, Gln, Ser, β-spiral shell-pip, Thr, Tba, Tle or Aib appoint It anticipates aforementioned corresponding Alpha-Methyl amino acid form；X14 be Phe, Tyr, Glu, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or β hPhe or arbitrary aforementioned corresponding Alpha-Methyl amino acid form；X15 be Gly, Ser, Thr、Gln、Ala、(D)Ala、(D)Asn、(D)Asp、(D)Leu、(D)Phe、(D)Thr、Aea、Asp、Asn、Glu、Phe、 Gly, Lys, Leu, Pro, Arg or Sarc or arbitrary aforementioned corresponding Alpha-Methyl amino acid form；X16 be Asp, Glu, Ala, AEA, AEP, β hAla, Gaba, Gly, Ser, Pro, Asn, Thr are not present or arbitrary aforementioned corresponding Alpha-Methyl amino acid Form；And X17 is Leu, Lys, Arg, Glu, Ser, Gly, Gln or is not present or arbitrary aforementioned corresponding Alpha-Methyl amino Sour form.

In certain embodiments, X4 and X9 is Pen.In a particular embodiment, X4 and X9 are cyclized via disulfide bond.

In certain embodiments, X4 Abu and X9 are Cys.In certain embodiments, X4 and X9 are via thioether Key is cyclized.

In a particular embodiment, X5 Ala, Arg, Glu, Phe, Leu, Thr, Ser, Aib, Sarc, D-Ala, D- Arg、D-Glu、D-Phe、D-Leu、D-Thr、D-Ser、D-Aib、Cys、Cit、Asp、Dab、Dap、Gly、His、hCys、Lys、 Met、Asn、N-Me-Ala、N-Me-Asn、N-Me-Lys、N-Me-Gln、Orn、Pro、Pen、Gln、Val、αMe-Lys、αMe- Orn or D-Sarc, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg or Gln.In certain embodiments, X5 is Gln or Asn.In a particular embodiment, X5 Ala, Arg, Glu, Phe, Leu, Thr、Ser、Aib、Sarc、D-Ala、D-Arg、D-Glu、D-Phe、D-Leu、D-Thr、D-Ser、D-Aib、Cys、Cit、Asp、 Dab、Dap、Gly、His、hCys、Lys、Met、Asn、N-Me-Ala、N-Me-Asn、N-Me-Lys、N-Me-Gln、N-Me- Arg, Orn, Pro, Pen, Gln, Val, α Me-Lys, α Me-Orn or D-Sarc.In certain embodiments, X5 Gln.

In a particular embodiment, X6 Asp, Thr, Asn, Phe, D-Asp, D-Thr, D-Asn, Glu, Arg, Ser or D-Phe.In a particular embodiment, X6 Thr.

In a particular embodiment, X7 Trp.

In a particular embodiment, X8 Val, Gln, Glu, Phe, Asn, Pro, Arg, Thr, Trp or Lys.Specific In embodiment, X8 Gln.

In a particular embodiment, X1, X2 and X3 are not present.

In certain embodiments, X11 is Trp analogs.

In a particular embodiment, X10 is Phe analogs.In a particular embodiment, X10 is Phe (4-OMe), Phe (4-CONH₂) or Phe [4- (2- amino ethoxies)] (being also referred to as Phe [4-2ae)] herein).In a particular embodiment, X10 is Phe (4-OMe) or Phe [4- (2- amino ethoxies)] (being also referred to as Phe [4-2ae)] herein).

In a particular embodiment, X11 is 2-Nal or 1-Nal.In certain embodiments, X11 2-Nal.

In certain embodiments, X12 be α-MeLys, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer or α- MeVal.In certain embodiments, X12 is α-MeLys.

In certain embodiments, X13 is Glu or Lys (Ac).In certain embodiments, X13 Glu.

In certain embodiments, X14 Asn.

In certain embodiments, X15 is Gly or Asn.In certain embodiments, X15 Gly.

In certain embodiments, one or more of X16, X17, X18, X19 and X20, two or more, three Or more or four or more be not present.In a particular embodiment, X16, X17, X18, X19 and X20 are not present.

In the specific embodiment of Ir, X4 and X9 are Cys, and X7 Trp and X18 are [(D) Lys].In the specific of Ir In embodiment, X4 and X9 are Cys, and X7 Trp, X10 Tyr and X18 are [(D) Lys].In the specific embodiment of Ir In, X4 and X9 are Cys, X7 Trp, and X1, X2 and X3 are not present, and X17 is not present, and X18 is [(D) Lys] and X19 and X20 is not In the presence of.In the specific embodiment of Ir, X4 and X9 are that Cys, X7 and X11 are Trp, and X10 Tyr and X18 are [(D) Lys. In certain embodiments, X1, X2 and X3 are not present；And in certain embodiments, X17 is not present.

In the specific embodiment of Ir, it is α-MeLys that X4 and X9, which are Pen and X12,.In the specific embodiment of Ir In, X4 and X9 are Pen, and X12 is that α-MeLys and X16, X17, X18, X19 and X20 are not present.In the specific embodiment of Ir In, X4 and X9 are Pen, X12 is α-MeLys, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal, X16, X17, X18, X19 It is not present with X20 and X7 is Trp.In the specific embodiment of Ir, X4 and X9 are Pen, X12 be α-MeLys, X16, X17, X18, X19 and X20 are not present and X7 is Trp.In the specific embodiment of Ir, X4 and X9 are Pen, X7 Trp, And X12 is α-MeLys.In certain embodiments, X1, X2 and X3 are not present.In a particular embodiment, between X4 and X9 There are disulfide bond.

In the specific embodiment of Ir, X4 Abu, X9 Cys and X12 be 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys or α-MeLys (Ac), α-Me-Leu, α- MeOrn, α-MeSer or α-MeVal.In the specific embodiment of Ir, X4 Abu, X9 Cys and X12 are α-MeLys. In the specific embodiment of Ir, X4 Abu, X9 Cys, X12 be α-MeLys, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys or α-MeLys (Ac), α-Me-Leu, α- MeOrn, α-MeSer or α-MeVal and X16, X17, X18, X19 and X20 are not present.In the specific embodiment of Ir, X4 For Abu, X9 Cys, X12 are α-MeLys and X16, X17, X18, X19 and X20 are not present.In the specific embodiment of Ir In, X4 Abu, X9 Cys, X12 be α-MeLys, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys or α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer or α-MeVal, X16, X17, X18, X19 and X20 are not present and X7 is Trp.In the specific embodiment of Ir, X4 Abu, X9 Cys, X12 is α-MeLys, and X16, X17, X18, X19 and X20 are not present and X7 is Trp.In the specific embodiment of Ir, X4 is Abu, X9 Cys, X7 Trp and X12 are α-MeLys.In certain embodiments, X1, X2 and X3 are not present.Specific In embodiment, there are thioether bonds between X4 and X9.

In certain embodiments of the inhibitor peptides of Formulas I, X includes the sequence of Formulas I s or is made from it：

X1-X2-X3-C-X5-X6-W-X8-C-X10-X11-X12-X13-X14-G-X16-X17-X18-X19-X20(Is)

Wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X5 is arbitrary amino acid；

X6 is arbitrary amino acid；

X8 is arbitrary amino acid；

X10 is Tyr, 1-Nal, 2-Nal, Phe (3,4-F₂), Phe (3,4-Cl₂), F (3-Me), Phe [4- (2- amino second Oxygroup)], Phe [4- (2- (acetyl-amino ethoxy)], Phe (4-Br), Phe (4-CONH₂)、Phe(4-Cl)、Phe(4- CN), Phe (4- guanidine radicals), Phe (4-Me), Phe (4-NH₂)、Phe(4-N₃), Phe (4-OMe), Phe (4-OBzl) or Tyr；

X11 is Trp, 1-Nal, Phe (3,4-OMe₂), 5- hydroxyls-Trp, Phe (3,4-Cl₂) or Tyr (3-t-Bu)；

X12 be Arg, Lys, His, hArg, Cit, Orn, 1-Nal, D-Ala, D-Leu, D-Phe, D-Asn, D-Asp, Agp, Leu, β hLeu, Aib, β hAla, β hVal, β hArg, hLeu, Dap, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α- MeSer, α-MeVal, Cha, Cit, Cpa, (D) Asn, Glu, hArg or Lys；

X13 be Cha, Ogl, Aib, Leu, Val, Dab, Glu, Lys, β hLeu, β hAla, β hVal, β Glu, Lys (Ac), Cit, Asp, Dab, Dap, Glu, hArg, Lys, Asn, Orn, Lys (Ac) or Gln；

X14 is Phe, Tic, Asn, Tyr, Asn, Arg, Qln, Lys (Ac), His；Dap (Ac), Dab (Ac) or Asp；

X16 is arbitrary amino acid；

X17 is not present；

X18 is D-Lys；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present.

In the specific embodiment of Is：X10 is Tyr, 1-Nal or 2-Nal；X11 is Trp or 1-Nal；X12 be Arg, Lys、His、hArg、Cit、Orn、1-Nal、D-Ala、D-Leu、D-Phe、D-Asn、D-Asp、Agp、Leu、βhLeu、Aib、β HAla, β hVal, β hArg, hLeu or Dap；X13 is Cha, Ogl, Aib, Leu, Val, Dab, Glu, Lys, β hLeu, β hAla, β HVal or β GLu；X14 is Phe, Tic, Asn or Tyr；And X16 is AEA, Ala or β Ala.

In a particular embodiment, X5 Glu, Arg, Ala, N-Me-Arg, N-Me-Ala, N-Me-Gln, Orn, N-Me- Asn, N-Me-Lys, Ser, Gln, Orn, Asn or Dap.In a particular embodiment, X5 Glu, Arg, Ala, N-Me-Arg, N-Me-Ala, N-Me-Gln, Orn, N-Me-Asn, N-Me-Lys, Ser, Asn or Dap.

In a particular embodiment, X6 is Asp or Thr.

In a particular embodiment, X8 is Gln or Val.

In a particular embodiment, the peptide of Is is cyclized via the disulfide bond between X4 and X9.

In certain embodiments of the inhibitor peptides of Formulas I, X includes the sequence of Formulas I t or is made from it：

X1-X2-X3-C-X5-X6-W-X8-C-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (It)

Wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X5 is arbitrary amino acid；

X6 is arbitrary amino acid；

X8 is arbitrary amino acid；

X10 is Tyr, 1-Nal, 2-Nal, Phe [4- (2- amino ethoxies)], Phe (4-CONH₂)、Phe(4-OMe)；

X11 is Trp, 1-Nal, 2-Nal, Bip, Phe (3,4-OMe₂), 5- hydroxyls-Trp；

X12 be Arg, His, 3-Pal, Leu, Thr, Gln, Asn, Glu, Ile, Phe, Ser, Lys, hLeu, α-MeLeu, D-Leu, D-Asn, h-Leu, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer or α-MeVal；

X13 is Thr, Glu, Tyr, Lys, Gln, Asn, Lys, Lys (Ac), Asp, Arg, Ala, Ser, Leu；

X14 is Phe, Tyr, Asn, Gly, Ser, Met, Arg, His, Lys, Leu or Gln；

X15 is Gly, Ser, Arg, Leu, Asp, Ala, β-Ala, Glu, Arg or Asn；

X16 is not present or is arbitrary amino acid；

X17 is not present or is arbitrary amino acid；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present.

In certain embodiments of It：X10 is Tyr, 1-Nal or 2-Nal；X11 is Trp, 1-Nal, 2-Nal or Bip； X12 is Arg, His, 3-Pal, Leu, Thr, Gln, Asn, Glu, Ile, Phe, Ser, Lys, hLeu, α-MeLeu, D-Leu, D- Asn or h-Leu；X13 is Thr, Glu, Tyr, Lys, Gln, Asn, Lys, Asp, Arg, Ala, Ser, Leu；X15 be Gly, Ser, Arg, Leu, Asp or Ala；X16 is not present or is Asn, Glu, Phe, Ala, Gly, Pro, Asp, Gln, Ser, Thr, D-Glu Or Lys；And X17 be not present or be Pro, Arg, Glu, Asp, Ser, Gly or Gln.

In a particular embodiment, X5 Ser, Asp, Asn, Gln, Ala, Met, Arg, His or Gly.It is being embodied In scheme, X5 Ser, Asp, Gln, Ala, Met, Arg, His or Gly.

In a particular embodiment, X6 is arbitrary Asp, Ser or Thr.

In a particular embodiment, X8 Gln, Glu or Thr.

In a particular embodiment, the peptide of It is cyclized via the disulfide bond between X4 and X9.

In another embodiment, the present invention include the inhibitor peptides of Interleukin-23 receptor or its pharmacy can The salt or solvate of receiving, wherein the inhibitor peptides include the amino acid sequence of formula (Va)：

(X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19- X20(Va)

Wherein,

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary D- amino acid or is not present；

X4 is Cys, hCys, Pen, hPen, Abu, Ser, hSer or can form the chemical part of key with X9；

X5 is Ala, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N- MeArg, Orn, Gln, Arg, Ser or Thr.

X6 is Thr, Ser, Asp, Ile or arbitrary amino acid；

X7 is Trp, 6- chloro- Trp, 1-Nap or 2-Nap；

X8 is Glu, Gln, Asn, Lys (Ac), Cit, Cav, Lys (N- ε-(N- α-palmityl-L- γ-glutamyls)) Or Lys (N- ε-palmityl)；

X9 is Cys, hCys, Pen, hPen, Abu or can form the chemical part of key with X4；

X10 is 2-Nal, Phe analog, Tyr or Tyr analogs；

X12 be Aib, 4- amino -4- carboxyls-oxinane, arbitrary Alpha-Methyl amino acid, α-ethyl-amino acid, Achc, Acvc, Acbc, Acpc, 4- amino -4- Carboxy-piperidins, 3-Pal, Agp, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-MeLeu、a-α-MeOrn、α-MeSer、α-MeVal、Cav、Cha、Cit、Cpa、D-Asn、Glu、His、hLeu、hArg、 Lys, Leu, Octgly, Orn, piperidines, Arg, Ser, Thr or THP；

X13 is Lys (Ac), Gln, Cit, Glu or arbitrary amino acid；

X14 be Asn, Gln, Lys (Ac), Cit, Cav, Lys (N- ε-(N- α-palmityl-L- γ-glutamyls)), Lys (N- ε-palmityl) or arbitrary amino acid；

X15 is β-Ala, Asn, Gly, Gln, Ala, Ser, Aib or Cit；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present,

Wherein X4 and X9 can form key each other.In a particular embodiment, the key is ehter bond, disulfide bond or thioether Key.In certain embodiments, inhibitor peptides are cyclized via the key between X4 and X9.

In certain embodiments, X1 is D- amino acid or is not present.In certain embodiments, X2 be D- amino acid or It is not present.

In certain embodiments, X16 is D- amino acid or is not present.In certain embodiments, X17 is D- amino acid Or it is not present.In certain embodiments, X18 is D- amino acid or is not present.In certain embodiments, X19 is D- amino Acid is not present.In certain embodiments, X20 is D- amino acid or is not present.

In the specific embodiment of formula (Ia), X10 2-Nal, Phe (3,4- bis- F₂), Phe (3,4-Cl₂)、Phe(3- Me), Phe [4- (2- amino ethoxies)], Phe [4- (2- acetyl-aminos ethyoxyl)], Phe (Br), Phe (4-CONH2), Phe (Cl), Phe (4-CN), Phe (4- guanidine radicals), Phe (4-Me), Phe (4-NH₂)、Phe(4-N₃), Tyr, Tyr (Bzl) or Tyr (Me).In certain embodiments of formula (Ia), X10 is Phe (4-ZR), Phe (3-ZR) or Phe (2-ZR), wherein R=CH₂ (CH₂)_nY and n=1-25, Z=NH, O, CO, CONH or CH₂, and Y=NH₂、CO₂H, OH or CH₃。

In further relevant embodiment, the present invention include Interleukin-23 receptor inhibitor peptides or its Pharmaceutically acceptable salt or solvate, wherein the inhibitor peptides include the amino acid sequence of formula (Vb)：

X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19- X20(Vb)

Wherein,

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is D-Arg, D-Phe, arbitrary D amino acid or is not present；

X4 is Cys, hCys, Pen, hPen, Abu or can form the chemical part of key with X9；

X5 be Gln, Asn, Lys (Ac), Cit, Cav, Lys (N- ε-(N- α-palmityl-L- γ-glutamyls)) or Lys (N- ε-palmityl).

X6 is Thr, Ser, Asp, Ile or arbitrary amino acid；

X7 is Trp, 1-Nap or 2-Nap；

X8 be Gln, Asn, Lys (Ac), Cit, Cav, Lys (N- ε-(N- α-palmityl-L- γ-glutamyls)) or Lys (N- ε-palmityl)；

X9 be Cys, hCys, Pen, hPen, Abu, can with X4 formed key arbitrary amino acid or chemical part；

X10 is Phe [4- (2- amino ethoxies)], Phe [4- (2- acetyl-aminos ethyoxyl)], Phe (4-CONH₂)、 Phe (4- guanidine radicals), Phe (4-NH₂), Tyr (Me) or Phe (4-ZR), wherein R=CH₂(CH₂)_nY；N=1-25；Z=O, CO, NH, CONH or CH₂；And Y=NH₂、CO₂H, OH or CH₃；

X11 is 2-Nal or Trp；

X12 is Aib, 4- amino -4- carboxyls-oxinane, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α - MeLeu, α-MeOrn, α-MeSer, α-MeVal, acid, Achc, Acvc, Acbc Acpc or 4- amino -4- Carboxy-piperidins；

X13 is Lys (Ac), Gln, Cit, Glu or arbitrary amino acid；

X15 is β-Ala, Asn, Gln, Ala, Ser or Aib；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present,

Wherein X4 and X9 can form key each other.In a particular embodiment, the key is disulfide bond or thioether bond.At certain In a little embodiments, inhibitor peptides are cyclized via the key between X4 and X9.

In another related embodiment, the present invention includes the inhibitor peptides or its pharmacy of Interleukin-23 receptor Acceptable salt or solvate, wherein the inhibitor peptides include the amino acid sequence of formula (Vc)：

X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19- X20(Vc)

Wherein,

X1 is not present；

X2 is not present；

X3 is D-Arg or is not present；

X4 is Cys, Pen, Abu or can form the chemical part of key with X9；

X5 is Gln, Asn, Lys (Ac), Cit or Cav；

X6 is Thr or Ser；

X7 is Trp, 1-Nap or 2-Nap；

X8 is Gln, Asn, Lys (Ac), Cit or Cav；

X9 is Cys, hCys, Pen, hPen, Abu or can form the arbitrary amino acid or chemical part of key with X4；

X10 is Phe [4- (2- amino ethoxies)], Phe (4-CONH2) or Phe (4-OR), wherein R=CH₂(CH₂)_nY；n =1-25；And Y=NH₂、CO₂H, OH or CH₃；

X11 is Trp or 2-Nal；

X12 be Aib, 4- amino -4- carboxyls-oxinane, α-MeLys, α-MeLys (Ac), α-MeLeu, Achc, Acvc, Acbc or Acpc；

X13 is Lys (Ac) or Glu；

X14 is Asn, Gln, Lys (Ac), Lys (N- ε-(N- α-palmityl-L- γ-glutamyls)) or Lys (N- ε- Palmityl).

X15 is Gly, β-Ala, Asn, Gln, Ala, Ser or Aib；

X16 is not present；

X17 is not present；

X18 is not present；

X19 is not present；And

X20 is not present,

In another relevant embodiment, the present invention includes the inhibitor peptides or its medicine of Interleukin-23 receptor Acceptable salt or solvate are learned, wherein the inhibitor peptides include the amino acid sequence of formula (Vd)：

X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19- X20(Vd)

Wherein,

X1 is not present；

X2 is not present；

X3 is not present；

X4 is Pen or Abu；

X5 is Gln or Asn；

X6 is Thr or Ser；

X7 is Trp；

X8 is Gln or Asn；

X9 is Pen or Cys；

X10 is Phe [4- (2- amino ethoxies)] or Phe (4-CONH₂)；

X11 is Trp or 2-Nal；

X12 is Aib, 4- amino -4- carboxyls-oxinane, α-MeLys, α-MeLeu or Achc；

X13 is Lys (Ac) or Glu；

X14 is Asn, Gln or Lys (Ac)；

X15 is Gly, Ala, Ser, β-Ala, Asn or Gln；

X16 is not present；

X17 is not present；

X18 is not present；

X19 is not present；And

X20 is not present,

Any inhibitor peptides (for example, any one of those of Formulas I (for example, Ix, Ia-It)) of the present invention can be with example Such as, it is further limited as described below.It should be understood that can be by each application described herein further limited in feature In any inhibitor peptides, wherein the amino acid specified in specific position, which allows to exist, further limits feature.

In certain embodiments, arbitrary Phe [4- (2- the amino ethoxies)] residue being present in inhibitor peptides can quilt Phe [4- (2- acetyl-aminos ethyoxyl)] replaces.

In certain embodiments, X1-X20 is the cyclisation Pen- relative to the illustrative inhibitor peptides listed in table 2-5 Pen is cyclized arbitrary amino acid shown in the corresponding position of Abu-Cys residues.

In certain embodiments, arbitrary inhibitor peptides as described herein (include but not limited to formula (X), (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg) or (Vh)) also include peptide arbitrary 2 amino acid residues between connector or introns Part.In a particular embodiment, the connector or spacer moiety are peg moiety.

In certain embodiments, inhibitor peptides are cyclized by disulphide bridges.

In certain embodiments, X10 Tyr, Phe [4- (2- amino ethoxies)], Phe (4-CONH₂) or Phe (4- OMe).In certain embodiments, X10 Tyr.

In certain embodiments, X11 2-Nal, Trp or 5- hydroxyls-Trp.In certain embodiments, X11 is Trp。

In certain embodiments, X10 is Tyr or Phe [4- (2- amino ethoxies)] and X11 is Trp or 2-Nal. In certain embodiments, X10 Tyr and X11 are Trp.

In a particular embodiment, X4 and X9 is Cys.

In a particular embodiment, it X4 Cys, Pen, hCys or is not present.

In a particular embodiment, X7 and X11 is not all W.

In a particular embodiment, X7 and X11 is W.

In a particular embodiment, X7 and X11 is W, and X10 Y and X4 and X9 are Cys.

In a particular embodiment, X15 Gly, Asn, β-ala or Ser.In a particular embodiment, X15 be Gly or Ser。

In a particular embodiment, X16 is AEA or AEP.

In a particular embodiment, X10 Tyr, Phe or Phe [4- (2- amino ethoxies).In a particular embodiment, X10 is Tyr or Phe.

In a particular embodiment, X11 is Trp or 2-Nal.In a particular embodiment, X11 Trp.

In a particular embodiment, X1, X2 and X3 are not present.

In a particular embodiment, X18, X19 and X20 are not present.

In a particular embodiment, X1, X2, X3, X18, X19 and X20 are not present.

In a particular embodiment, one or more of X1, X2 or X3 are existing.

In the specific embodiment of any one of Ix, I α-Ir, one of X1, X2 and X3 be existing and other two not In the presence of.In one embodiment, existing X1, X2 or X3 are Ala.

In certain embodiments, X3 is existing.In a particular embodiment, X3 Glu, (D) Glu, Arg, (D) Arg、Phe、(D)Phe、2-Nal、Thr、Leu、(D)Gln.In certain embodiments, X3 is (D) Arg or (D) Phe.Having In body embodiment, X1 and X2 is not present and X3 is existing.

In a particular embodiment, two in X1, X2 and X3 are existing and remaining one is not present.Certain In embodiment, existing two are made of SG, NK, DA, PE, QV or DR.

In a particular embodiment, X1, X2 and X3 are existing.In certain embodiments, X1, X2 and X3 by ADQ, KEN, VQE, GEE, DGF, NAD, ERN, RVG, KAN or YED are formed.

In certain embodiments, peptide includes AEP residues.In a particular embodiment, X15, X16, X17, X18, X19 or Any of X20 is AEP.

In certain embodiments of any inhibitor peptides or peptide monomer subunit, X13 Thr, Sarc, Glu, Phe, Arg, Leu, Lys, Lys (Ac), β hAla or Aib.In certain embodiments of any inhibitor peptides or peptide monomer subunit, X13 is Thr, Sarc, Glu, Phe, Arg, Leu, Lys, β hAla or Aib.In certain embodiments, X14 Phe, Asn, Tyr or β hPhe.In certain embodiments, X14 Phe, Tyr or β hPhe.In certain embodiments, X15 Gly, Asn, Ser, Thr, Gln, Ala or Sarc.In certain embodiments, X15 Gly, Ser, Thr, Gln, Ala or Sarc. In certain embodiments, X12 is alpha amino acid, for example, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer or α-MeVal.

In certain embodiments, X13 is existing.

In certain embodiments, X13 and X14 is existing.

In certain embodiments, X13, X14 and X15 are existing.

In the specific embodiment of any of Ia-It, one or more of X16-X20 is existing.Having In body embodiment, two or more or three or more in X16-X20 are existing.In specific embodiment In, X18 is [(D) Lys].In a particular embodiment, X17 is not present and X18 is [(D) Lys].X4 and X9 appoints wherein Selection of land is in certain embodiments of Cys, and X4 and X9 are Cys, and X7 Trp and X18 are [(D) Lys].X4 and X9 wherein It is optionally in the specific embodiment of Cys, X4 and X9 are Cys, and X7 Trp, X10 are Tyr or Phe [4- (2- amino ethoxies Base)] and X18 be [(D) Lys].It is optionally in the specific embodiment of Cys in wherein X4 and X9, X4 and X9 are Cys, X7 It is [(D) Lys] for Trp, X10 Tyr and X18.Be optionally in the specific embodiment of Cys in wherein X4 and X9, X4 and X9 is Cys, X7 Trp, and X1, X2 and X3 are not present, and X17 is not present, and X18 is that [(D) Lys] and X19 and X20 are not present. In the specific embodiment of Ir, X4 and X9 are that Cys, X7 and X11 are Trp, and X10 Tyr and X18 are [(D) Lys.Certain In embodiment, X1, X2 and X3 are not present；And in certain embodiments, X17 is not present.

In certain embodiments, any inhibitor peptides (or monomelic subunit) described herein are cyclisation.Specific In embodiment, inhibitor peptides are cyclized via the key between two or more internal amino acids of inhibitor peptides.Specific real It applies in scheme, the inhibitor peptides of cyclisation are cyclized via the key between the ends N- of inhibitor peptides and C-terminal amino acid.At certain In a little embodiments, it is Amino-terminal amino acid residue to participate in one of amino acid residue of intramolecular bond for making peptide be cyclized.Certain In embodiment, arbitrary inhibitor peptides are cyclized via the peptide bond between its n terminal amino acid and its C-terminal amino acid.

In any inhibitor peptides either certain embodiments of one or both monomelic subunit inhibitor peptides (or One or both monomelic subunit) via between X4 and X9 intramolecular bond or be cyclized by triazole ring.In specific embodiment party In case, intramolecular bond is any one of disulfide bond, thioether bond, lactam bond, triazole key, selenide key, two selenium keys or alkene key.

In one embodiment, the X4 in inhibitor peptides (or one or both monomelic subunit) and X9 be Cys, Pen, hCys, D-Pen, D-Cys or D-hCys and intramolecular bond are disulfide bond.In certain embodiments, X4 and X9 are Cys or X4 and X9 is Pen and intramolecular bond is disulfide bond.

In one embodiment, the X4 in inhibitor peptides (or one or both monomelic subunit) and X9 be Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu or D-Lys and intramolecular bond are lactam bond.

In one embodiment, X4 Abu, 2- chloromethyl benzoic acids, mercaptopropionic acid, mercaptobutyric acid, the chloro- acetic acid of 2-, The chloro- propionic acid of 3-, the chloro- butyric acid of 4- or the chloro- isobutyric acids of 3-；X9 is Abu, Cys, Pen, hCys, D-Pen, D-Cys or D-hCys；With And intramolecular bond is thioether bond.In certain embodiments, X4 Abu and X9 are Pen and intramolecular bond is thioether bond. In a particular embodiment, X4 is the 2- methyl benzoyls part of thioether bond can be formed with X9, and X9 is selected from Cys, N- Me-Cys, D-Cys, hCys, Pen and D-Pen.In a particular embodiment, X4 Abu and X9 are Cys and intramolecular Key is thioether bond.In the specific example of the peptide monomer of any formula described herein and peptide, dimer or its subunit, X4 is selected from The Ser of modification, hSer (for example, height-Ser-Cl), suitable isostere and the corresponding D- amino acid of modification.In other examples In, X4 be with one to four carbon and with X9 formed thioether bond aliphatic acid.In some instances, X4 be with X9 formed sulphur Five yuan or hexa-atomic alicyclic acid of the 2- methyl of the modification of ehter bond.In some embodiments, X4 is 2- methyl benzoyls part. In certain embodiments, X4 is selected from Cys, hCys, Pen and 2- methyl benzoyl part.In certain embodiments, X4 is selected From the Ser of modification, the hSer of modification, suitable isostere and corresponding D- amino acid.In one embodiment, X4 is HSerCl (before thus removing Cl with X9 formation thioether bonds) or hSer precursors are (for example, high Ser (O-TBDMS).In other realities Example in, X4 be with one to four carbon and with X9 formed thioether bond aliphatic acid.In some instances, X4 is with being formed with X9 Five yuan or hexa-atomic alicyclic acid of the 2- methyl of the modification of thioether bond.In some instances, X4 is 2- methyl benzoyls part. Wherein X4 is not amino acid but in certain embodiments of chemical part for being combined with X9, X1, X2 and X3 are not present and X4 It is conjugated or combines with X5.In some embodiments, it is aromatic amino acid with the amino acid of the direct carboxylated of X9.In certain realities It applying in scheme, X4 is amino acid, and in other embodiments, X4 is that can be combined with X9, for example, to form the another of thioether bond One chemical part.In a particular embodiment, X4 is selected from herein for the another of any non-amino acid part described in X4 Chemical part.In the specific embodiment that wherein X4 is another chemical part, X1, X2 and X3 are not present and described another Chemical part is combined or is conjugated with X5.In certain embodiments, X4 is defined to include the chemistry of the group of such as chloride Part, for example, the chloro- acetic acid of 2- chloromethyl benzoic acids, 2-, 3- chloropropionic acids, 4- chloro-butyric acids, 3- chlorine isobutyric acids.However, technical staff Understand, once peptide has undergone cyclization cyclisation to form thioether bond between X4 and X9, then chloride group no longer exists.Therefore, Including the description of the chemical part at the X4 of the reactant group of such as chloride means the group with chloride and does not have The group (that is, after forming key with X9) of chloride.The invention also includes comprising with any other formula described herein or Mutually isostructural peptide shown in table, but wherein thioether bond is in opposed orientation.In such embodiment of the present invention, lead to It is often considered, amino acid residue shown in X4 or other chemical parts are present in amino shown in X9 and X9 instead Sour residue is present in X4 instead, that is, the amino acid residue of the sulphur comprising gained thioether bond is located at X4 rather than X9, and having can The amino acid residue of the carbon side chain of thioether bond is formed with X4 or other parts are located at X9.However, in the opposed orientation, X9 Amino acid or chemical part are amino acid or chemical part comprising unhindered amina.For example, in a particular embodiment, positioned at X9's Amino acid is shielded homoserine, e.g., for example, homoserine (OTBDMS).Therefore, in any formula described herein In the embodiment of the specific opposed orientation of inhibitor peptides, X9 is to be formed with the side chain containing one or two carbon, and with X4 The amino acid residue and X4 of thioether bond are selected from Cys, N-Me-Cys, D-Cys, HCys, Pen and D-Pen.This document describes deposit It is the specific example of the amino acid residue and other chemical parts of the corresponding position of other formulas and table.

It will be appreciated by those skilled in the art that when being combined with another molecule, certain amino acid and other chemical parts are modified. For example, when amino acid side chain and another amino acid side chain form the bridge of intramolecular, can be modified, for example, one or more A hydrogen can be removed or be replaced by key.In addition, when hSer-Cl is combined with the amino acid of such as Cys or Pen via thioether bond When, the parts Cl are released.Therefore, as used herein, the amino acid or modification being present in peptide dimer of the invention are referred to It is deposited in peptide before and after amino acid (such as hSer-Cl) (for example, at X4 or X9) means to be included in form intramolecular bond Such amino acid or modification amino acid form.

In certain embodiments, inhibitor peptides of the invention (or one or both monomelic subunit) pass through triazole ring Cyclisation.In certain embodiments, inhibitor peptides of the invention (either one or both monomelic subunit) be it is linear or It is not cyclisation.In the certain of any inhibitor peptides (including monomer inhibitor peptides and dimer peptide inhibitor) described herein In embodiment, (or two) peptide monomer subunit includes cyclisation peptide or is made from it, the cyclisation peptide with Ix, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, In, Io, Ip, Iq, Iq ', Ir, Is or It, IIa-IId, IIIa-IIIe, Structure or sequence shown in any one in Iva or IVb.

In certain embodiments of any inhibitor peptides or monomelic subunit, X7 and X11 are W.

In certain embodiments of any inhibitor peptides or monomelic subunit, X7 and X11 are not all W.In specific embodiment party In case, X7 W and X11 are not W.

In certain embodiments of any inhibitor peptides or monomelic subunit, X4 and X9 are that can form intramolecular bond each other Amino acid residue, the intramolecular bond be thioether bond, lactam bond, triazole key, selenide key, two selenium keys or alkene key.

In certain embodiments, X7 and X11 is W, X10 Y, Phe [4- (2- amino ethoxies) or Phe (CONH₂), and X4 and X9 is the amino acid residue that can form intramolecular bond each other, and the intramolecular bond is thioether bond, interior Amido bond, triazole key, selenide key, two selenium keys or alkene key.In certain embodiments, X7 and X11 is W, X10 Y, and X4 and X9 is the amino acid residue that can form intramolecular bond each other, and the intramolecular bond is thioether bond, lactam bond, triazole Key, selenide key, two selenium keys or alkene key.

In certain embodiments, X7 and X11 is W, and X10 Y and X4 and X9 are C.

In certain embodiments, X4 and X9 is respectively Cys, Pen, hCys, D-Pen, D-Cys or D-hCys, and divides Sub- internal key is disulfide bond.

In certain embodiments, X4 and X9 are respectively Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D- Asp, D-Glu or D-Lys, and intramolecular bond is lactam bond.

In certain embodiments, X4 and X9 is respectively β-azido-Ala-OH or propargylglycine, and peptide inhibits Agent (or monomelic subunit) is cyclized by triazole ring.

In certain embodiments, X4 and X9 is respectively 2- allylglycines, 2- (3 '-cyclobutenyl) glycine, 2- (4 '-pentenyl) glycine or 2- (5 '-hexenyl) glycine, and inhibitor peptides (or monomelic subunit) are via cyclization double decomposition Reaction cyclisation is to generate corresponding alkene/" stapler peptide (stapled peptide) ".

In certain embodiments, X4 is 2- chloromethyl benzoic acids, mercaptopropionic acid, mercaptobutyric acid, the chloro- acetic acid of 2-, 3- chloro- The chloro- butyric acid of propionic acid, 4-, the chloro- isobutyric acids of 3- or hSer (Cl)；X9 be hSer (Cl), Cys, Pen, hCys, D-Pen, D-Cys or D-hCys；And intramolecular bond is thioether bond.In certain embodiments, X4 is 2- chloromethyl benzoic acids or hSer (Cl)；X9 For Cys or Pen, and intramolecular bond is thioether bond.In certain embodiments, X4 Abu and X9 are Cys or Pen.

In certain embodiments, X4 is 2- chloromethyl benzoic acids, the chloro- acetic acid of 2-, the chloro- propionic acid of 3-, the chloro- butyric acid of 4-, 3- Chloro- isobutyric acid, Abu or Sec；X9 is Abu or Sec；And intramolecular bond is selenide key.

In certain embodiments, the intramolecular bond between X4 and X9 is two selenium keys.

It is described herein containing two amino acid residues connected by intramolecular bond (for example, disulfide bond) (for example, Cysteine residues) any inhibitor peptides certain embodiments in, participate in two amino acid residues of intramolecular bond not all Positioned at the ends N- of inhibitor peptides or C- end positions.In certain embodiments, two amino acid residue (examples of intramolecular bond are participated in Such as, cysteine) it is not located at the ends N- or the C- end positions of inhibitor peptides.In other words, in certain embodiments, molecule is participated in At least one of two amino acid residues (for example, cysteine) of internal key or the internal amino acid that two are inhibitor peptides are residual Base.In certain embodiments, two amino acid residues (for example, cysteine) for participating in intramolecular bond are not located at peptide inhibition The C- end positions of agent.In a certain embodiment, two amino acid residues for participating in intramolecular bond are Cys, Pen, hCys, D- Pen, D-Cys or D-hCys residue.In certain embodiments, participate in intramolecular bond two amino acid residues be located at X4 and X9.In one embodiment, there are two sulphur between the amino acid residue at X4 and X9 (for example, cysteine or Pen residues) Key.In a particular embodiment, X4 and X9 is Pen.In certain embodiments, one or two of inhibitor peptides peptide list Body subunit is cyclized via the disulfide bond between two Pen residues at such as X4 and X9.

In the specific embodiment of any inhibitor peptides described herein, being present in inhibitor peptides, (no matter it is single Body or dimer) one or two of peptide monomer subunit, for example, by being present in two in peptide monomer or peptide monomer subunit Intramolecular bond (such as disulfide bond) cyclization between a cysteine or cyclisation.In certain embodiments, inhibitor peptides include two A or more cysteine residues.In some embodiments, inhibitor peptides are via the intramolecular between two cysteines Disulfide bond is cyclized.In the specific embodiment of the inhibitor peptides with any formula described herein, two cysteines are deposited It is X4 and X9.In other embodiments, one or two of inhibitor peptides peptide monomer subunit is via such as X4 Disulfide bond cyclisation between two Pen residues at X9.

In some embodiments, inhibitor peptides have the structure and packet of any formula (for example, Formulas I) described herein Containing disulfide bond, for example, intramolecular disulfide bond or thioether bond.The illustrative examples of such inhibitor peptides be shown in table 3A-3H and table 4A, Table 4B, table 9, table 11 or table 15.The peptide of such disulfide bonding can have specific advantages, be, the disulfide bond enhancing Structural stability and the bioactivity that many biologically active peptides can be improved.However, in some cases, these keys are to reduction Agent is unstable.It will be appreciated by those skilled in the art that disulphide is suitble to simple equal rows' replacement.The illustrative examples packet of such replacement Include but be not limited to, thioether, disulfide, selenide, diselenide, triazole, lactams, alkane and alkene group.Therefore, herein In certain embodiments of described any inhibitor peptides, one, two or more cysteine residues for example by thioether, Group (the including but not limited to shown below or sheet of disulfide, selenide, diselenide, triazole, lactams, alkane and alkene Any one of those described in literary) substitution.In a particular embodiment, two formation keys in the group of these substitutions (for example, intramolecular bond) is thus cyclized inhibitor peptides or one or both monomelic subunit.

In certain embodiments, inhibitor peptides of the invention include following or are made up of：Herein, such as in table Any of 3A-3H, table 4A, table 4B, table 5A-5C, table 6, table 7, table 8, table 9, table 10, table 11, table 12, table 13, table 14 or table 15 Amino acid sequence shown in a.In certain embodiments, inhibitor peptides of the invention have herein, such as in table 3A- In either one or two of 3H, table 4A, table 4B, table 5A-5C, table 6, table 7, table 8, table 9, table 10, table 11, table 12, table 13, table 14 or table 15 Shown in structure.

In certain embodiments, the present invention includes comprising the core consensus sequence selected from following one (with the ends N- to C- Extreme direction is shown) inhibitor peptides：

X₁X₂X₂WX₂X₁X₂W；

X₁X₂X₂WX₂X₁X₂(1-Nal)；

X₁X₂X₂WX₂X₁X₂(2-Nal)；

X₁X₂X₂WX₂X₁YW；

X₁X₂X₂WX₂X₁Y(1-Nal)；

X₁X₂X₂WX₂X₁Y(2-Nal)；

X₁X₂X₂WX₂X₁X₂X₂；

X₁X₂X₂WX₂X₁X₂X₂X₂X₂X₂-[(D)Lys]；

X₁X₂X₂WX₂X₁X₃X₂；

X₁X₂X₂WX₂X₁X₃(1-Nal)；And

X₁X₂X₂WX₂X₁X₃(2-Nal)。

Wherein W is tryptophan, and Y is tyrosine, and two X1 residues are respectively can be with the amino of formation intramolecular bond each other Sour or other chemical parts；Each X2 is independently selected from all amino acid comprising, for example, natural amino acid, l-amino acid, D- amino acid, non-natural amino acid and non-natural amino acid；And X3 is arbitrary amino acid.In a particular embodiment, X3 is Phe, Phe analog are (for example, Phe [4- (2- amino ethoxies)] or Phe (4-CONH₂)), Tyr or Tyr analogs (for example, Tyr(Me)).In a particular embodiment, each X1 is selected from Cys, Pen and Abu.In a particular embodiment, each X1 is Cys.In certain embodiments, each X1 is Pen.In certain embodiments, an X1 is Cys, and another X1 is Abu. In specific embodiment, the ends N- X1 is that the ends Abu and C- X1 is Cys.In a particular embodiment, the ends N- X1 is Cys, and The ends C- X1 is Abu.In a particular embodiment, the residue between two X1 residues is Gln, Thr, Trp and Gln.Specific real It applies in scheme, each X1 is selected from Cys, Pen and Abu；And X3 be Phe, Phe analog (for example, Phe [4- (2- amino ethoxies Base)] or Phe (4- ureas)), Tyr or Tyr analogs (for example, Tyr (Me)).In a particular embodiment, X3 is Phe analogs.

In certain embodiments, inhibitor peptides of the invention include any following consensus sequences, wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14 and X15 are as described herein in any various or inhibitor peptides Shown definition：

X1-X2-X3-Pen-X5-X6-W-X8-Pen-X10-X11-X12-X13-X14-X15；

Pen-X5-X6-W-Q-Pen；

Pen-X5-X6-W-X8-Pen；

Pen-X5-X6-W-X8-Pen-[Phe(4-CONH2)]；

Pen-X5-X6-W-X8-Pen- [Phe [4- (2- amino ethoxies)]]；

X1-X2-X3-Abu-X5-X6-W-X8-C-X9-X10-X11-X12-X13-X14-X15；

Abu-X5-X6-W-Q-C；

Abu-X5-X6-W-X8-C；

Abu-X5-X6-W-X8-C-[Phe(4-CONH2)]；Or

Abu-X5-X6-W-X8-C- [Phe [4- (2- amino ethoxies)]].

In certain embodiments of any inhibitor peptides or monomelic subunit, X7 and X11 are W.In any inhibitor peptides Certain embodiments in, X7 and X11 are that W and X10 is Y.In certain embodiments, X7 and X11 is W, and X10 is Phe [4- (2- amino ethoxies)] or Phe (4-OMe).

In certain embodiments of any inhibitor peptides or monomelic subunit, X7 and X11 are not all W.

In certain embodiments of the inhibitor peptides of Formulas I, X4 and X9 are respectively Pen, and intramolecular bond is disulfide bond.

In certain embodiments, inhibitor peptides of the invention are included in either one or two of table, sequence table or the attached drawing of this paper Shown in amino acid sequence or be made from it.

It is described herein containing two amino acid residues connected by intramolecular bond (for example, disulfide bond) (for example, Pen residues) any inhibitor peptides certain embodiments in, participate in one or both of two amino acid residues of intramolecular bond It is not located at the ends N- or the C- end positions of inhibitor peptides.In certain embodiments, two amino acid residues of intramolecular bond are participated in (for example, Pen) is not located at the ends N- or the C- end positions of inhibitor peptides.In other words, in certain embodiments, intramolecular is participated in At least one of two amino acid residues (for example, Pen) of key or the internal amino acid residue that two are inhibitor peptides.At certain In a little embodiments, two amino acid residues (for example, Pen) for participating in intramolecular bond are not located at the ends the C- position of inhibitor peptides It sets.

In some embodiments, wherein the acidification of the peptide of the present invention and such as isovaleric acid, isobutyric acid, valeric acid etc. It is conjugated to close object, such conjugated presence is mentioned as the acid.Thus, for example, but do not limit in any way, at some In embodiment, the application refers to such be conjugated for isovaleric acid-[Pen]-QTWQ [Pen]-[Phe (4-OMe)]-[2- Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂Instead of by referring to that isovaleryl indicates the conjugated of isovaleric acid and peptide, for example, Isovaleryl-[Pen]-QTWQ [Pen]-[Phe (4-OMe)]-[2-Nal]-[α-MeLys]-[Lys (Ac)]-NG-NH₂。

The invention also includes with existing epitope or binding structural domain in the amino acid residue 230-349 of people's IL23R albumen The inhibitor peptides of selective binding.In a particular embodiment, inhibitor peptides combination people IL23R but hyperkine R is not combined. In certain embodiments, inhibitor peptides are also combined with rat IL-23R.

In certain embodiments of the inhibitor peptides of Formulas I, X4 Abu；X9 is Cys, Pen, high cys, and intramolecular Key is thioether bond.

In certain embodiments, inhibitor peptides are not included in PCT application the PCT/US2014/030352nd or the Shens PCT It please compound disclosed in No. PCT/US2015/038370.

Include the exemplary peptides inhibitor of Pen-Pen disulfide bond

In certain embodiments, the present invention, which includes the inhibitor peptides of Interleukin-23 receptor or its pharmacy, to connect The salt or solvate received, wherein inhibitor peptides have the structure of Formula II：

R¹-X-R²(II)

Wherein R¹For key, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, C1-C20 hydrocarbon acyl group, Hydrocarbyl sulfonate, acid, γ-Glu or pGlu (being added into the ends N-), and include the individual Pegylation of aforementioned any one Form or PEGylated forms (for example, 200Da to 60,000Da) as introns；

R²For key, OH or NH₂；And

X is the amino acid sequence of 8 to 20 amino acid or 8 to 35 amino acid.

In the specific embodiment of the inhibitor peptides of Formula II, X includes the sequence of Formula II a or is made from it：

X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19- X20(IIa)

Wherein

X1 is not present or is arbitrary amino acid；

X2 is not present or is arbitrary amino acid；

X3 is not present or is arbitrary amino acid；

X4 is Pen, Cys or high-Cys；

X5 is arbitrary amino acid；

X6 is arbitrary amino acid；

X7 is Trp, Bip, Gln, His, Glu (Bzl), 4- phenylbenzyls alanine, Tic, Phe [4- (2- amino ethoxies Base)], Phe (3,4-Cl₂), Phe (4-OMe), 5- hydroxyls-Trp, chloro- Trp, N-MeTrp, α-Me-Trp of 6-, 1,2,3,4- tetra- Hydrogen-norharmane, Phe (4-CO₂H)、Phe(4-CONH₂), Phe (3,4- dimethoxy), Phe (4-CF₃)、Phe(4- TBu), β β-two PheAla, Glu, Gly, Ile, Asn, Pro, Arg, Thr or Octgly or arbitrary aforementioned corresponding Alpha-Methyl Amino acid form；

X8 is arbitrary amino acid；

X9 is Pen, Cys or hCys；

X10 be 1-Nal, 2-Nal, Aic, Bip, (D) Cys, Cha, DMT, (D) Tyr, Glu, Phe, His, Trp, Thr, Tic, Tyr, 4- pyridyl group Ala, Octgly, Phe analog or Tyr analogs (optionally, (3,4-F Phe₂), Phe (3,4- Cl₂), F (3-Me), Phe [4- (2- amino ethoxies)], Phe [4- (2- (acetyl-amino ethoxy)], Phe (4-Br), Phe (4-CONH₂), Phe (4-Cl), Phe (4-CN), Phe (4- guanidine radicals), Phe (4-Me), Phe (4-NH₂)、Phe(4-N₃)、Phe (4-OMe) or Phe (4-OBzl)) or arbitrary aforementioned corresponding Alpha-Methyl amino acid form；

X11 is 2-Nal, 1-Nal, 2,4- dimethyl Phe, Bip, Phe (3,4-Cl₂), Phe (3,4-F₂)、Phe(4- CO₂H), β hPhe (4-F), α-Me-Trp, 4- phenylcyclohexyls, Phe (4-CF₃)、α-MePhe、βhNal、βhPhe、βhTyr、β HTrp, Nva (5- phenyl), Phe, His, hPhe, Tic, Tqa, Trp, Tyr, Phe (4-OMe), Phe (4-Me), Trp (2,5,7- Three-tertiary butyls), Phe (4-O allyls), Tyr (3-tBu), Phe (4-tBu), Phe (4- guanidine radicals, Phe (4-OBzl), Octgly, Glu (Bzl), 4- phenylbenzyls alanine, Phe [4- (2- amino ethoxies)], 5- hydroxyls-Trp, 6- chloro- Trp, N- MeTrp, 1,2,3,4- tetrahydrochysenes-norharmane, Phe (4-CONH₂), Phe (3,4-OMe₂), Phe (2,3-Cl₂), Phe (2,3- F₂), Phe (4-F), 4- phenylcyclohexyls alanine or Bip or arbitrary aforementioned corresponding Alpha-Methyl amino acid form；

X12 be α-MeLys, α-MeOrn, α-MeLeu, α-MeVal, 4- amino -4- carboxyls-oxinane, Achc, Acpc、Acbc、Acvc、MeLeu、Aib、(D)Ala、(D)Asn、(D)Leu、(D)Asp、(D)Phe、(D)Thr、3-Pal、Aib、 β-Ala, β hGlu, β hAla, β hLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Phe、hLeu、hArg、hLeu、Ile、Lys、Leu、Asn、N-MeLeu、N-MeArg、Ogl、Orn、Pro、Gln、Arg、Ser、 Thr or Tle or arbitrary aforementioned corresponding Alpha-Methyl amino acid form；

X13 be Lys (Ac), (D) Asn, (D) Leu, (D) Tbr, (D) Phe, Ala, Aib, α-MeLeu, β-Ala, β hGlu, β hAla, β hLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Lys, Arg, Orn, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, Lys, Leu, Asn, Ogl, Pro, Gln, Asp, Arg, Ser, spiral shell-pip, Thr, Tba, Tlc, Val or Tyr or Arbitrary aforementioned corresponding Alpha-Methyl amino acid form；

X14 be Asn, Glu, Phe, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr, Lys (Ac), the aforementioned corresponding Alpha-Methyl amino acid forms of Orn or arbitrary；

X15 be Gly, (D) Ala, (D) Asn, (D) Asp, Asn, (D) Leu, (D) Phe, (D) Thr, Ala, AEA, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg or Ser, β-Ala, the aforementioned corresponding Alpha-Methyl amino acid shapes of Arg or arbitrary Formula；

X16 is not present, and is Gly, Ala, Asp, Ser, Pro, Asn or Thr or arbitrary aforementioned corresponding Alpha-Methyl amino Sour form；

X17 is not present, and is Glu, Ser, Gly or Gln or arbitrary aforementioned corresponding Alpha-Methyl amino acid form；

X18 is not present or is arbitrary amino acid；

X19 is not present or is arbitrary amino acid；And

X20 is not present or is arbitrary amino acid.

In certain embodiments of IIa：X10 be 1-Nal, 2-Nal, Aic, Bip, (D) Cys, Cha, DMT, (D) Tyr, Glu, Phe, His, Trp, Thr, Tic, Tyr, 4- pyridyl group Ala, Octgly, Phe analog or Tyr analogs or it is arbitrary before State corresponding Alpha-Methyl amino acid form；X11 is 2-Nal, 1-Nal, 2,4- dimethyl Phe, Bip, Phe (3,4-Cl₂)、Phe (3,4-F₂)、Phe(4-CO₂H), β hPhe (4-F), α-Me-Trp, 4- phenylcyclohexyls, Phe (4-CF₃)、α-MePhe、β HNal, β hPhe, β hTyr, β hTrp, Nva (5- phenyl), Phe, His, hPhe, Tic, Tqa, Trp, Tyr, Phe (4-OMe), Phe (4-Me), Trp (2,5,7- tri--tertiary butyl), Phe (4-O allyls), Tyr (3-tBu), Phe (4-tBu), Phe (4- guanidines Base, Phe (4-OBzl), Octgly, Glu (Bzl), 4- phenylbenzyls alanine, Phe [4- (2- amino ethoxies)], 5- hydroxyls- The chloro- Trp, N-MeTrp of Trp, 6-, 1,2,3,4- tetrahydrochysenes-norharmane, Phe (4-CONH₂), Phe (3,4- dimethoxy), Phe (2,3-Cl₂), Phe (2,3-F₂), Phe (4-F), 4- phenylcyclohexyls alanine or Bip or arbitrary aforementioned corresponding α- Methylamino acid form；X12 be α-MeLys, α-MeOrn, α-MeLeu, MeLeu, Aib, (D) Ala, (D) Asn, (D) Leu, (D) Asp, (D) Phe, (D) Thr, 3-Pal, Aib, β-Ala, β hGlu, β hAla, β hLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu, N- MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr or Tle or arbitrary aforementioned corresponding Alpha-Methyl amino acid form；X13 For Lys (Ac), (D) Asn, (D) Leu, (D) Thr, (D) Phe, Ala, Aib, α-MeLeu, β-Ala, β hGlu, β hAla, β HLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Lys, Arg, Orn, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, Lys, Leu, Asn, Ogl, Pro, Gln, Asp, Arg, Ser, spiral shell-pip, Thr, Tba, Tlc, Val or Tyr or arbitrary aforementioned right The Alpha-Methyl amino acid form answered；X14 be Asn, Glu, Phe, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr or arbitrary aforementioned corresponding Alpha-Methyl amino acid form；And X15 is Gly, (D) Ala, (D) Asn、(D)Asp、Asn、(D)Leu、(D)Phe、(D)Thr、Ala、AEA、Asp、Glu、Phe、Gly、Lys、Leu、Pro、Gln、 Arg or Ser or arbitrary aforementioned corresponding Alpha-Methyl amino acid form.

In certain embodiments, X5 Gln, Ala, Cit, Asp, Dab, Dap, Cit, Glu, Phe, Gly, His, hCys、Lys、Leu、Met、Asn、N-Me-Ala、N-Me-Asn、N-Me-Lys、α-Me-Lys、αMe-Orn、N-Me-Gln、N- Me-Arg, α-MeSer, Orn, Pro, Arg, Ser, Thr or Val.In certain embodiments, X5 Gln, Ala, Cit, Asp, Dab、Dap、Glu、Phe、Gly、His、hCys、Lys、Leu、Met、Asn、N-Me-Ala、N-Me-Asn、N-Me-Lys、α-Me- Lys, α-Me-Orn, N-Me-Gln, N-Me-Arg, Orn, Pro, Arg, Ser, Thr or Val.In certain embodiments, X5 is Gln or Asn.

In certain embodiments, X6 Thr, Asp, Glu, Phe, Asn, Pro, Arg or Ser.

In certain embodiments, X7 Trp.

In certain embodiments, X8 Gln, Glu, Phe, Lys, Asn, Pro, Arg, Val, Thr or Trp.

In certain embodiments, X10 is Tyr analogs or Phe analogs.In a particular embodiment, X10 Phe Analog.

Wherein X10 be Phe analogs certain embodiments in, X10 be selected from hPhe, Phe (4-OMe), α-Me-Phe, HPhe (3,4- dimethoxy), Phe (4-CONH₂), Phe (4- phenoxy groups), Phe (4- guanidine radicals), Phe (4-tBu), Phe (4- CN)、Phe(4-Br)、Phe(4-OBzl)、Phe(4-NH₂), Phe (4-F), Phe (3,5 two F), Phe (CH₂CO₂H)、Phe(5- F), (3,4-Cl Phe₂)、Phe(4-CF₃), β β-two PheAla, Phe (4-N₃) and Phe [4- (2- amino ethoxies)].Specific In embodiment, X10 is Phe (4-OMe) or Phe [4- (2- amino ethoxies)].In a particular embodiment, X10 Phe (4-OMe)、Phe(4-CONH₂) or Phe [4- (2- amino ethoxies)].X10 is certain embodiment party of Phe analogs wherein In case, X10 is selected from hPhe, Phe (4-OMe), α-Me-Phe, hPhe (3,4- dimethoxy), Phe (4-CONH₂), Phe (4- benzene Oxygroup), Phe (4- guanidine radicals), Phe (4-tBu), Phe (4-CN), Phe (4-Br), Phe (4-OBzl), Phe (4-NH₂)、Phe (4-F), Phe (3,5 two F), Phe (CH₂CO₂H), Phe (5-F), Phe (3,4-Cl₂)、Phe(4-CF₃), β β-two PheAla, Phe(4-N₃) and Phe [4- (2- amino ethoxies)].In a particular embodiment, X10 is Phe (4-OMe).

In certain embodiments that wherein X10 is Tyr analogs, X10 is selected from hTyr, α-MeTyr, N-Me-Tyr, Tyr (3-tBu)、Phe(4-CONH₂), Phe [4- (2- amino ethoxies)] and β hTyr.X10 is the certain of Tyr analogs wherein In embodiment, X10 is selected from hTyr, α-MeTyr, N-Me-Tyr, Tyr (3-tBu) and bhTyr.

In certain embodiments, X10 Tyr, Phe (4-OMe), Phe [4- (2- amino ethoxies)], Phe (4- CONH₂) or 2-Nal.In certain embodiments, X10 is Phe (4-OMe) or Phe [4- (2- amino ethoxies)].Certain In embodiment, X10 is not Tyr.

In certain embodiments, X11 is Trp analogs.In a particular embodiment, X11 is 2-Nal or 1-Nal. In certain embodiments, X11 2-Nal.

In certain embodiments, X12 Aib, α-MeLys or α-MeLeu.

In the specific embodiment of the inhibitor peptides of Formula II, one or both of X4 or X9 are Pen.In specific embodiment In, X4 and X9 are Pen.

In certain embodiments, the inhibitor peptides of Formula II are cyclisation.In a particular embodiment, the peptide of Formula II inhibits Agent is cyclized via the intramolecular bond between X4 and X9.In a particular embodiment, intramolecular bond is disulfide bond.In specific embodiment party In case, X4 and X9 are Pen.

In certain embodiments, the inhibitor peptides of Formula II are linear or are not cyclisation.Press down in the linear peptides of Formulas I In the specific embodiment of preparation, X4 and/or X9 are arbitrary amino acid.

In the specific embodiment of the inhibitor peptides of Formula II, one or more of X1, X2 and X3, two or more Or whole three is not present.In certain embodiments, X1 is not present.In certain embodiments, X1 and X2 are not present. In certain embodiments, X1, X2 and X3 are not present.

In the specific embodiment of the inhibitor peptides of Formula II, one or more of X16, X17, X18, X19 and X20, Two or more, three or more, four or more or be entirely absent.In the specific reality of the inhibitor peptides of Formulas I Apply in scheme, one or more of X17, X18, X19 and X20, two or more, three or more or all do not deposit .In certain embodiments, one or more of X17, X19 and X20, two or more or all three do not deposit .In certain embodiments, one or more of X1, X2 and X3 are not present；And one in X17, X18, X19 and X20 It is a or multiple, two or more, three or more or four are not present.

In the specific embodiment of the inhibitor peptides of Formula II, X18 is (D)-Lys.In certain embodiments, X18 is (D)-Lys and X17 are not present.

In the specific embodiment of the inhibitor peptides of Formula II, inhibitor peptides include one or more of following characteristics, Two or more, three or more or four：X5 is Asn, Arg or Gln；X6 is Thr；X7 is Trp；And X8 is Gln.In the specific embodiment of the inhibitor peptides of Formulas I, X4 Pen；X5 is Gln, Asn or Arg；X6 is Thr；X7 be Trp, 5- hydroxyls-Trp, 6- chloro- Trp, N-MeTrp, α-Me-Trp or 1,2,3,4- tetrahydrochysenes-norharmane；X8 is Gln；And X9 For Pen.In a particular embodiment, X5 Gln.In certain embodiments, X1, X2 and X3 are not present.In specific embodiment party In case, X4 and X9 are Pen.

In the specific embodiment of the inhibitor peptides of Formula II, inhibitor peptides include one or more of following characteristics, Two or more, three or more, four or more, five or more, six or more or seven：X10 For Tyr, Phe analog, Tyr analogs or 2-Nal；X11 is chloro- Trp, N-MeTrp, α-Me- of Trp, 5- hydroxyl-Trp, 6- Trp, 1,2,3,4- tetrahydrochysenes-norharmane, 2-Nal or 1-Nal；X12 is Aib, α-MeLys, α-MeOrn and α-MeLeu； X13 is Lys, Glu or Lys (Ac)；X14 is Phe or Asn；X15 is Gly, Ser or Ala；And X16 be not present or be AEA. In certain embodiments, X10 Tyr, Phe (4-OMe), Phe [4- (2- amino ethoxies)], Phe (CONH₂) or 2-Nal. In certain embodiments, X11 is 2-Nal or 1-Nal.In certain embodiments, X10 is not Tyr.In certain embodiments In, X1, X2 and X3 are not present.In a particular embodiment, X4 and X9 is Pen.

In the specific embodiment of the inhibitor peptides of Formula II, inhibitor peptides include one or more of following characteristics, Two or more, three or more, four or more, five or more, six or more, seven or more It is a, eight or more, nine or more, ten or more or 11：X5 is Arg or Gln；X6 is Thr；X7 is Trp；X8 is Gln；X10 is Phe analogs；X11 is Trp, 2-Nal or 1-Nal；X12 is Aib, α-MeLys or α-MeOrn； X13 is Lys, Glu or Lys (Ac)；X14 is Asn；X15 is Gly, Ser or Ala；And X16 be not present or be AEA.Certain In embodiment, X10 is Phe (4-OMe) or Phe [4- (2- amino ethoxies)].In certain embodiments, X11 2-Nal Or 1-Nal.In certain embodiments, X1, X2 and X3 are not present.In a particular embodiment, X4 and X9 is Pen.

In the specific embodiment of the inhibitor peptides of Formula II, peptide is cyclized via X4 and X9；X4 and X9 is Pen；X5 is Gln；X6 is Thr；X7 is Trp；X8 is Gln；X10 is Tyr, Phe analog or 2-Nal；X11 is Trp, 2-Nal or 1-Nal； X12 is Arg, α-MeLys, α-MeOrn or α-MeLeu；X13 is Lys, Glu or Lys (Ac)；X14 is Phe or Asn；X15 is Gly, Ser or Ala；And X16 is not present.In certain embodiments, X10 Tyr, Phe (4-OMe), Phe [4- (2- amino Ethyoxyl)], Phe (4-OMe) or 2-Nal.In certain embodiments, X10 is Phe (4-OMe).In certain embodiments, X10 is not Tyr.In certain embodiments, X11 is 2-Nal or 1-Nal.In certain embodiments, X1, X2 and X3 are not deposited .

In the specific embodiment of the inhibitor peptides of Formula II, peptide is cyclized via X4 and X9；X4 and X9 is Pen；X5 is Gln；X6 is Thr；X7 is Trp；X8 is Gln；X10 is Tyr, Phe (4-OMe) or 2-Nal；X11 is Trp, 2-Nal or 1-Nal； X12 is Arg, α-MeLys or α-MeOrn；X13 is Lys, Glu or Lys (Ac)；X14 is Phe or Asn；X15 is Gly；And X16 is not present.In certain embodiments, X10 is Phe (4-OMe).In certain embodiments, X11 is 2-Nal or 1- Nal.In certain embodiments, X1, X2 and X3 are not present.

In the specific embodiment of the inhibitor peptides of Formula II, peptide is cyclized via X4 and X9；X4 and X9 is Pen；X5 is Gln；X6 is Thr；X7 is Trp；X8 is Gln；X10 is Phe (4-OMe) or Phe [4- (2- amino ethoxies)]；X11 be Trp, 2-Nal or 1-Nal；X12 is α-MeLys, α-MeOrn or α-MeLeu；X13 is Lys, Glu or Lys (Ac)；X14 is Asn；X15 For Gly, Ser or Ala；And X16 is not present.In certain embodiments, X10 is Phe (4-OMe).In certain embodiments In, X11 is 2-Nal or 1-Nal.In certain embodiments, X1, X2 and X3 are not present.

In the specific embodiment of the inhibitor peptides of Formula II, X10 is not Tyr.

In certain embodiments, the present invention include the length being optionally cyclized be optionally 8 to 35,8 to 20,8 to 16 A or 8 to 12 amino acid peptide, it includes the core sequence of Formula II b or is made from it：

Pen-Xaa5-Xaa6-Trp-Xaa8-Pen-Xaa10-[(2-Nal)](IIb)

Wherein Xaa5, Xaa6 and Xaa8 are arbitrary amino acid residue；And Xaa10 is Phe analogs, wherein the peptide presses down The combination of IL-23 and IL-23R processed.In a particular embodiment, X10 is Phe analogs, is selected from α-Me-Phe, Phe (4- OMe)、Phe(4-OBzl)、Phe(4-OMe)、Phe(4-CONH₂), Phe (3,4-Cl₂)、Phe(4-tBu)、Phe(4-NH₂)、 Phe(4-Br)、Phe(4-CN)、Phe(4-CO₂H), Phe [4- (2- amino ethoxies)] or Phe (4- guanidine radicals).It is being embodied In scheme, Xaa10 is Phe (4-OMe) or Phe [4- (2- amino ethoxies)].In one embodiment, Xaa10 Phe (4-OMe).In certain embodiments, the peptide is cyclized via the intramolecular bond between the Pen of the Pen and Xaa9 of Xaa4. In specific embodiment, the peptide is the inhibitor peptides of Formula II, and wherein in certain embodiments, X1, X2 and X3 are not deposited .In a particular embodiment, the peptide inhibits the combination of IL-23 and IL-23R.In certain embodiments, the peptide of Formula II b Also include the amino acid combined with the ends N- Pen residues.In a particular embodiment, in conjunction with amino acid be Glu, (D) Glu, Arg, (D) Arg, Phe, (D) Phe, 2-Nal, Thr, Leu or (D) Gln.In certain embodiments, it is (D) Arg or (D) Phe。

In certain embodiments, the present invention include the length being optionally cyclized be optionally 8 to 35,8 to 20,8 to 16 A or 8 to 12 amino acid peptide, it includes the core sequence of Formula II c or is made from it：

Pen-Xaa5-Xaa6-Trp-Xaa8-Pen-Xaa10-[(2-Nal)](IIc)

Wherein Xaa5, Xaa6 and Xaa8 are arbitrary amino acid residue；And Xaa10 is Tyr, Phe analogs, α-Me- Tyr, α-Me-Trp or 2-Nal, wherein the peptide inhibits the combination of IL-23 and IL-23R.In certain embodiments, X10 is Tyr, Phe (4-OMe), Phe [4- (2- amino ethoxies)], α-Me-Tyr, α-Me-Phe, α-Me-Trp or 2-Nal.Certain In embodiment, Xaa10 Tyr, Phe (4-OMe), Phe (CONH₂), Phe [4- (2- amino ethoxies)] or 2-Nal.At certain In a little embodiments, Xaa10 Tyr, Phe (4-OMe), Phe [4- (2- amino ethoxies)] or 2-Nal.In specific embodiment party In case, Xaa10 is Phe (4-OMe) or Phe [4- (2- amino ethoxies)].In one embodiment, Xaa10 is Phe [4- (2- amino ethoxies)] or Phe (CONH₂).In a particular embodiment, Xaa10 is Phe (4-OMe) or Phe [4- (2- amino Ethyoxyl)].In one embodiment, Xaa10 is Phe [4- (2- amino ethoxies)].In certain embodiments, Xaa10 It is not Tyr.In certain embodiments, the peptide is cyclized via the intramolecular bond between the Pen of the Pen and Xaa9 of Xaa4. In specific embodiment, the peptide is the inhibitor peptides of Formula II, and wherein in certain embodiments, X1, X2 and X3 are not deposited .In a particular embodiment, the peptide inhibits the combination of IL-23 and IL-23R.In certain embodiments, the peptide of Formula II c Also include the amino acid combined with the ends N- Pen residues.In a particular embodiment, in conjunction with amino acid be Glu, (D) Glu, Arg, (D) Arg, Phe, (D) Phe, 2-Nal, Thr, Leu or (D) Gln.In certain embodiments, it is (D) Arg or (D) Phe。

In certain embodiments, the present invention include the length being optionally cyclized be optionally 8 to 35,8 to 20,8 to 16 A or 8 to 12 amino acid peptide, it includes the core sequence of Formula II d or is made from it：

Pen-Xaa5-Xaa6-Trp-Xaa8-Pen-Phe [4- (2- amino ethoxies)]-[2-Nal] (IId)

Wherein Xaa5, Xaa6 and Xaa8 are arbitrary amino acid residue.In certain embodiments, peptide be included in Xaa4 and Disulfide bond between Xaa9.In certain embodiments, the peptide is the inhibitor peptides of Formulas I, and wherein in certain embodiment party In case, X1, X2 and X3 are not present.In a particular embodiment, the peptide inhibits the combination of IL-23 and IL-23R.In certain realities It applies in scheme, the peptide of Formula II d also includes the amino acid combined with the ends N- Pen residues.In a particular embodiment, in conjunction with amino Acid is Glu, (D) Glu, Arg, (D) Arg, Phe, (D) Phe, 2-Nal, Thr, Leu or (D) Gln.In certain embodiments, It is (D) Arg or (D) Phe.

In the specific embodiment of the inhibitor peptides of Formula II, inhibitor peptides have any table 2,3,4A, table 4B, table 8, table 11 or table 15 shown in structure or include amino acid sequence shown in table 2, table 3, table 4A, table 4B, table 8, table 11 or table 15 Row.

2. illustrative Di-Pen inhibitor of table

Exemplary peptides of the table 3. containing Ac- [Pen]-XXWX- [Pen]-XXXX motifs and the like

Include the exemplary peptides inhibitor of thioether bond

In certain embodiments, the present invention, which includes the inhibitor peptides of Interleukin-23 receptor or its pharmacy, to connect The salt or solvate received, wherein inhibitor peptides have the structure of formula III：

R¹-X-R²(III)

R²For key, OH or NH₂；And

X is the amino acid sequence of 8 to 20 amino acid or 8 to 35 amino acid,

In the specific embodiment of the inhibitor peptides of formula III, X includes the sequence of formula III a or is made from it：

X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19- X20(IIIa)

Wherein

X1 is not present or is arbitrary amino acid；

X2 is not present or is arbitrary amino acid；

X3 is not present or is arbitrary amino acid；

X4 is Abu, Pen or Cys；

X5 is arbitrary amino acid；

X6 is arbitrary amino acid；

X7 is Trp, Bip, Gln, His, Glu (Bzl), 4- phenylbenzyls alanine, Tic, Phe [4- (2- amino ethoxies Base)], Phe (3,4-Cl₂), Phe (4-OMe), 5- hydroxyls-Trp, chloro- Trp, N-MeTrp, α-MeTrp of 6-, 1,2,3,4- tetra- Hydrogen-norharmane, Phe (4-CO₂H)、Phe(4-CONH₂), Phe (3,4- (OCH₃)₂)、Phe(4-CF₃), β β-two PheAla, Phe (4-tBu), Glu, Gly, Ile, Asn, Pro, Arg, Thr or Octgly or arbitrary aforementioned corresponding Alpha-Methyl amino acid Form；

X8 is arbitrary amino acid；

X9 is Abu, Pen or Cys；

X10 be 1-Nal, 2-Nal, Aic, Bip, (D) Cys, Cha, DMT, (D) Tyr, Glu, Phe, His, Trp, Thr, Tic, Tyr, 4- pyridyl group Ala, Octgly, Phe analog or Tyr analogs (optionally, (3,4-F Phe₂), Phe (3,4- Cl₂), F (3-Me), Phe [4- (2- amino ethoxies)], Phe [4- (2- (acetyl-amino ethoxy)], Phe (4-Br), Phe (4-CONH₂), Phe (4-Cl), Phe (4-CN), Phe (4- guanidine radicals), Phe (4-Me), Phe (4-NH₂)、Phe(4-N₃)、Phe (4-OMe), Phe (4-OBzl)) or arbitrary aforementioned corresponding Alpha-Methyl amino acid form；

X11 is 2-Nal, 1-Nal, 2,4- dimethyl Phe, Bip, 4- phenylcyclohexyl, Glu (Bzl), 4- phenylbenzyls third Propylhomoserin, Tic, Phe [4- (2- amino ethoxies)], Phe (3,4-Cl₂), Phe (3,4-F₂)、βhPhe(4-F)、Phe(4-OMe)、 Chloro- Trp, N-MeTrp, α-MeTrp of 5- hydroxyls-Trp, 6-, 1,2,3,4- tetrahydrochysenes-norharmane, Phe (4-CO₂H)、Phe (4-CONH₂), Phe (3,4- dimethoxy), Phe (4-CF₃), Phe (2,3-Cl₂), Phe (3,4-Cl₂), Phe (2,3-F₂)、 Phe (4-F), 4- phenylcyclohexyls alanine, α-MePhe, β hNal, β hPhe, β hTyr, β hTrp, Bip, Nva (5- phenyl), Phe, His, hPhe, Tqa, Trp, Tyr, Phe (4-Me), Trp (2,5,7- tri--tertiary butyl), Phe (4-O allyls), Tyr (3- TBu), Phe (4-tBu), Phe (4- guanidine radicals), Phe (4-OBzl) or Octgly or arbitrary aforementioned corresponding Alpha-Methyl amino acid Form；

X12 be α-MeLys, α-MeOrn, α-MeLeu, MeLeu, Aib, (D) Ala, (D) Asn, (D) Leu, (D) Asp, (D) Phe, (D) Thr, 3-Pal, Aib, β-Ala, β hGlu, β hAla, β hLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr or Tle, amino -4- carboxyls-oxinane (THP), Achc, Acpc, Acbc, The aforementioned corresponding Alpha-Methyl amino acid form of Acvc, Aib or arbitrary；

X13 is Lys, Lys (Ac), (D) Asn, (D) Leu, (D) Thr, (D) Phe, Ala, Aib, α-MeLeu, β Ala, β HGlu, β hAla, β hLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Arg, Orn, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, Lys, Leu, Asn, Ogl, Pro, Gln, Asp, Arg, Ser, spiral shell-pip, Thr, Tba, Tlc, Val or Tyr or Arbitrary aforementioned corresponding Alpha-Methyl amino acid form；

X14 be Asn, Glu, Phe, Gly, His, Lys, Lys (Ac), Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic, Asp or Tyr or arbitrary aforementioned corresponding Alpha-Methyl amino acid form；

X15 be Gly, (D) Ala, (D) Asn, (D) Asp, Asn, (D) Leu, (D) Phe, (D) Thr, Ala, AEA, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg, β-Ala or Ser or arbitrary aforementioned corresponding Alpha-Methyl amino acid form；

X18 is not present or is arbitrary amino acid；

X19 is not present or is arbitrary amino acid；And

X20 is not present or is arbitrary amino acid.

In certain embodiments, X14 Asn, Glu, Phe, Gly, His, Lys, Lys (Ac), Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr, or arbitrary aforementioned corresponding Alpha-Methyl amino acid form.

In certain embodiments of IIIa：X7 be Trp, Bip, Gln, His, Glu (Bzl), 4- phenylbenzyls alanine, Tic, Phe [4- (2- amino ethoxies)], Phe (3,4-Cl₂), Phe (4-OMe), 5- hydroxyls-Trp, 6- chloro- Trp, N- MeTrp, α-MeTrp, 1,2,3,4- tetrahydrochysenes-norharmane, Phe (4-CO₂H)、Phe(4-CONH₂), Phe (3,4- dimethoxies Base), Phe (4-CF₃), β β-two PheAla, Phe (4-tBu), Glu, Gly, Ile, Asn, Pro, Arg, Thr or Octgly or Arbitrary aforementioned corresponding Alpha-Methyl amino acid form；X10 is 1-Nal, 2-Nal, Aic, Bip, (D) Cys, Cha, DMT, (D) Tyr, Glu, Phe, His, Trp, Thr, Tic, Tyr, 4- pyridyl group Ala, Octgly, Phe analog or Tyr analogs are appointed It anticipates aforementioned corresponding Alpha-Methyl amino acid form；X11 be 2-Nal, 1-Nal, 2,4- dimethyl Phe, Bip, 4- phenylcyclohexyl, Glu (Bzl), 4- phenylbenzyls alanine, Tic, Phe [4- (2- amino ethoxies)], Phe (3,4-Cl₂), Phe (3,4-F₂)、β HPhe (4-F), Phe (4-OMe), 5- hydroxyls-Trp, chloro- Trp, N-MeTrp, α-MeTrp of 6-, 1,2,3,4- tetrahydrochysenes-first is gone to breathe out You are full, Phe (4-CO₂H)、Phe(4-CONH₂), Phe (3,4- dimethoxy), Phe (4-CF₃), Phe (2,3-Cl₂), Phe (2, 3-F₂), Phe (4-F), 4- phenylcyclohexyls alanine, α-MePhe, β hNal, β hPhe, β hTyr, β hTrp, Bip, Nva (5- Phenyl), Phe, His, hPhe, Tqa, Trp, Tyr, Phe (4-Me), Trp (2,5,7- tri--tertiary butyl), Phe (4-O allyls), Tyr (3-tBu), Phe (4-tBu), Phe (4- guanidine radicals), Phe (4-OBzl) or Octgly or arbitrary aforementioned corresponding Alpha-Methyl Amino acid form；X12 is α-MeLys, α-MeOrn, α-MeLeu, MeLeu, Aib, (D) Ala, (D) Asn, (D) Leu, (D) Asp, (D) Phe, (D) Thr, 3-Pal, Aib, β-Ala, β hGlu, β hAla, β hLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu, N- MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr or Tle or arbitrary aforementioned corresponding Alpha-Methyl amino acid form；X13 For Lys (Ac), (D) Asn, (D) Leu, (D) Thr, (D) Phe, Ala, Aib, α-MeLeu, β Ala, β hGlu, β hAla, β hLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Arg, Orn, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, Lys, Leu, Asn, Ogl, Pro, Gln, Asp, Arg, Ser, spiral shell-pip, Thr, Tba, Tlc, Val or Tyr or arbitrary aforementioned corresponding α-first Base amino acid form；X14 is Asn, Glu, Phe, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic Or Tyr or arbitrary aforementioned corresponding Alpha-Methyl amino acid form；And X15 be Gly, (D) Ala, (D) Asn, (D) Asp, Asn, (D) Leu, (D) Phe, (D) Thr, Ala, AEA, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg or Ser or Arbitrary aforementioned corresponding Alpha-Methyl amino acid form.

In certain embodiments, X3 is existing.In a particular embodiment, X3 Glu, (D) Glu, Arg, (D) Arg, Phe, (D) Phe, 2-Nal, Thr, Leu or (D) Gln.In certain embodiments, it is (D) Arg or (D) Phe.

In a particular embodiment, X5 Gln, Ala, Cys, Cit, Asp, Dab, Dap, Glu, Phe, Gly, His, hCys、Lys、Leu、Met、Asn、N-Me-Ala、N-M-Asn、N-Me-Lys、N-Me-Gln、N-Me-Arg、Orn、Pro、Pen、 Gln, Arg, Ser, Thr or Val.

In a particular embodiment, X6 Thr, Asp, Glu, Phe, Asn, Pro, Arg, Ser or Thr.

In a particular embodiment, X8 Gln, Glu, Phe, Lys, Asn, Pro, Arg, Val, Thr or Trp.

In certain embodiments, X10 is Tyr analogs or Phe analogs.In a particular embodiment, X10 Phe (4-OMe)、Phe(CONH₂) or Phe [4- (2- amino ethoxies)].In certain embodiments, X10 be Tyr analogs or Phe analogs.In a particular embodiment, X10 is Phe (4-OMe) or Phe [4- (2- amino ethoxies)].

Wherein X10 be Phe analogs certain embodiments in, X10 be selected from hPhe, Phe (4-OMe), α-MePhe, HPhe (3,4- dimethoxy), Phe (4-CONH₂), Phe (4-O-Bzl)), Phe (4- guanidine radicals), Phe (4-tBu), Phe (4- CN)、Phe(4-Br)、Phe(4-NH₂), Phe (4-F), Phe (3,5 two F), Phe (CH₂CO₂H), Phe (5-F), Phe (3,4- Cl₂), Phe (4-CF3), β β-two PheAla, Phe (4-N₃) and Phe [4- (2- amino ethoxies)].In a particular embodiment, X10 is Phe [4- (2- amino ethoxies)] or Phe (CONH₂).In a particular embodiment, X10 is Phe [4- (2- amino second Oxygroup)].

Wherein X10 be Tyr analogs certain embodiments in, X10 be selected from hTyr, N-Me-Tyr, Tyr (3-tBu), Phe (4-OMe) and bhTyr.In a particular embodiment, X10 is Phe (4-OMe).

In a particular embodiment, X10 Tyr, Phe (4-OMe), Phe (4-OBzl), Phe (4-OMe), Phe (4- CONH₂), Phe (3,4-Cl₂), Phe (4-tBu), Phe (4-NH2), Phe (4-Br), Phe (4-CN), Phe (4- carboxyls), Phe [4- (2 amino ethoxy)] or Phe (4- guanidine radicals).In a particular embodiment, X10 is not Tyr.

In certain embodiments, X11 is Trp or Trp analogs.In a particular embodiment, X11 is 2-Nal or 1- Nal。

In a particular embodiment, the inhibitor peptides of formula III are cyclisation.In certain embodiments, inhibitor peptides pass through By the intramolecular bond cyclisation between X4 and X9.In certain embodiments, intramolecular bond is thioether bond.

In certain embodiments, the inhibitor peptides of formula III are linear or are not cyclisation.In the linear of formula III In the specific embodiment of inhibitor peptides, X4 and/or X9 are arbitrary amino acid.

In the specific embodiment of the inhibitor peptides of formula III, one or more of X1, X2 and X3, two or more A or whole three is not present.In certain embodiments, X1 is not present.In certain embodiments, X1 and X2 are not deposited .In certain embodiments, X1, X2 and X3 are not present.

In the specific embodiment of the inhibitor peptides of formula III, one or more of X16, X17, X18, X19 and X20, Two or more, three or more, four or more or all be not present.In the tool of the inhibitor peptides of formula III In body embodiment, one or more of X17, X18, X19 and X20, two or more, three or more or all It is not present.In certain embodiments, one or more of X17, X19 and X20, two or more or all three It is not present.In certain embodiments, one or more of X1, X2 and X3 are not present；And X17, X18, X19 and X20 One or more of, two or more, three or more or four are not present.

In the specific embodiment of the inhibitor peptides of formula III, one of X4 or X9 are another in Abu and X4 or X9 A is not Abu.In certain embodiments, X4 Abu and X9 are Cys.

In a particular embodiment, the inhibitor peptides of formula III include one or more of following characteristics, two or more A, three or more or four：X5 is Arg or Gln；X6 is Thr；X7 is Trp；And X8 is Gln.In specific embodiment party In case, X5 Gln, X6 Thr, X7 Trp and X8 are Gln.In certain embodiments, X5 Gln.In certain implementations In scheme, X1, X2 and X3 are not present.In certain embodiments, X4 Abu and X9 are Cys.

In a particular embodiment, the inhibitor peptides of formula III include one or more of following characteristics, two or more It is a, three or more, four or more, five or more, six or more or seven：X10 is Tyr or Phe Analog；X11 is Trp, 2-Nal, 1-Nal, Phe (4-O- allyls), Tyr (3-tBu), Phe (4-tBu), Phe (4- guanidines Base), Phe (4-OBzl) or Phe (4-Me)；X12 is Arg, hLeu, (D) Asn or arbitrary α methylamino acids, the α methyl ammonia Base acid includes Aib, α-MeLys, α-MeLeu or α-MeOrn；X13 is Lys, Glu or Lys (Ac)；X14 is Phe or Asn； X15 is β-Ala, Gln, Gly, Ser, Ala；And X16 be not present or be AEA.In a particular embodiment, the peptide suppression of formula III Preparation include one or more of following characteristics, two or more, three or more, four or more, five or More, six or more or seven：X10 is Tyr or Phe analogs；X11 is Trp, 2-Nal, 1-Nal, Phe (4-O- Allyl), Tyr (3-tBu), Phe (4-tBu), Phe (4- guanidine radicals), Phe (4-OBzl) or Phe (4-Me)；X12 be Arg, HLeu, (D) Asn or arbitrary α methylamino acids, the α methylamino acids include Aib, α-MeLys, α-MeLeu or α-MeOrn； X13 is Lys, Glu or Lys (Ac)；X14 is Phe or Asn；X15 is Gly, Ser, Ala；And X16 be not present or be AEA. In certain embodiments, Phe analogs are Phe (4-OBzl), Phe (4-OMe), Phe (4-CONH₂), Phe (3,4-Cl₂)、Phe (4-tBu), Phe (4-NH2), Phe (4-Br), Phe (4-CN), Phe (4- carboxyls), Phe [4- (2 amino ethoxy)] or Phe (4- guanidine radicals).In certain embodiments, X11 is 2-Nal or 1-Nal.In certain embodiments, X1, X2 and X3 are not present. In certain embodiments, X4 Abu and X9 are Cys.

In a particular embodiment, the inhibitor peptides of formula III include one or more of following characteristics, two or more It is a, three or more, four or more, five or more, six or more or seven：X10 is Tyr or Phe Analog；X11 is Trp, 2-Nal, 1-Nal, Phe (4-O- allyls), Tyr (3-tBu), Phe (4-tBu), Phe (4- guanidines Base), Phe (4-OBzl) or Phe (4-Me)；X12 be Arg, hLeu, (D) Asn, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α- MeSer、α-MeVal；X13 is Lys, Glu or Lys (Ac)；X14 is Phe or Asn；X15 is Gly；And X16 is not present or is AEA.In certain embodiments, Phe analogs are Phe (4-OBzl), Phe (4-OMe), Phe (4-CONH₂), Phe (3,4- Cl2)、Phe(4-tBu)、Phe(4-NH₂), Phe (4-Br), Phe (4-CN), Phe (4- carboxyls), Phe (4- (2 amino ethoxies Base)) or Phe (4- guanidine radicals).In certain embodiments, X11 is 2-Nal or 1-Nal.In certain embodiments, X1, X2 and X3 is not present.In certain embodiments, X4 Abu and X9 are Cys.

In a particular embodiment, the inhibitor peptides of formula III include one or more of following characteristics, two or more It is a, three or more, four or more, five or more, six or more, seven or more, eight or more It is multiple, nine or more, ten or more or 11：X5 is Arg or Gln；X6 is Thr；X7 is Trp；X8 is Gln；X10 is Phe analogs；X11 is Trp, 2-Nal, 1-Nal, Phe (4-O- allyls), Tyr (3-tBu), Phe (4- TBu), Phe (4- guanidine radicals), Phe (Bzl) or Phe (4-Me)；X12 is Aib, α-MeLys, α-MeLeu, 4- amino -4- carboxyls - Oxinane, Achc, Acpc, Acbc, Acvc, Agp, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me- Leu、α-MeSer、α-MeVal、α-MeOrn；X13 is Lys, Glu or Lys (Ac)；X14 is Phe or Asn；X15 be β-ala, Gly、Ser、Ala；And X16 be not present or be AEA.In a particular embodiment, the inhibitor peptides of formula III include following characteristics One or more of, two or more, three or more, four or more, five or more, six or more It is a, seven or more, eight or more, nine or more, ten or more or 11：X5 be Arg or Gln；X6 is Thr；X7 is Trp；X8 is Gln；X10 is Phe analogs；X11 is Trp, 2-Nal, 1-Nal, Phe (4-O- allyls Base), Tyr (3-tBu), Phe (4-tBu), Phe (4- guanidine radicals), Phe (Bzl) or Phe (4-Me)；X12 is Aib, α-MeLys, α- MeLeu or α-MeOrn；X13 is Lys, Glu or Lys (Ac)；X14 is Phe or Asn；X15 is Gly, Ser, Ala；And X16 is not In the presence of or for AEA.In certain embodiments, Phe analogs are Phe (4-OBzl), Phe (4-OMe), Phe [4- (2 amino second Oxygroup)], Phe (4-CONH₂), Phe (3,4-Cl₂)、Phe(4-tBu)、Phe(4-NH₂)、Phe(4-Br)、Phe(4-CN)、Phe (4-CO₂) or Phe (4- guanidine radicals) H.In certain embodiments, X11 is 2-Nal or 1-Nal.In certain embodiments, X1, X2 and X3 are not present.In certain embodiments, X4 Abu and X9 are Cys.

In a particular embodiment, the inhibitor peptides of formula III include one or more of following characteristics, two or more It is a, three or more, four or more, five or more, six or more, seven or more, eight or more It is multiple, nine or more, ten or more or 11：X5 is Arg or Gln；X6 is Thr；X7 is Trp；X8 is Gln；X10 is Tyr or Phe analogs；X11 is Trp, 2-Nal, 1-Nal, Phe (4-O- allyls), Tyr (3-tBu), Phe (4-tBu), Phe (4- guanidine radicals), Phe (Bzl) or Phe (4-Me)；X12 is Arg, hLeu, (D) Asn, 4- amino -4- carboxyls-four Hydrogen pyrans, Achc, Acpc, Acbc, Acvc, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α- MeSer、α-MeVal；X13 is Lys, Glu or Lys (Ac)；X14 is Phe or Asn；X15 is β-Ala, Asn or Gly；And X16 Be not present or be AEA.In a particular embodiment, the inhibitor peptides of formula III include one or more of following characteristics, two Or more, three or more, four or more, five or more, six or more, seven or more, eight It is a or more, nine or more, ten or more or 11：X5 is Arg or Gln；X6 is Thr；X7 is Trp； X8 is Gln；X10 is Tyr or Phe analogs；X11 be Trp, 2-Nal, 1-Nal, Phe (4-O- allyls), Tyr (3-tBu), Phe (4-tBu), Phe (4- guanidine radicals), Phe (Bzl) or Phe (4-Me)；X12 is Arg, hLeu, (D) Asn, α-MeLys, α- MeLeu or α-MeOrn, Aib；X13 is Lys, Glu or Lys (Ac)；X14 is Phe or Asn；X15 is Gly；And X16 is not present Or it is AEA.In certain embodiments, Phe analogs are Phe (4-OBzl), Phe (4OMe), Phe (4-CONH₂), Phe (3, 4-Cl₂)、Phe(4-tBu)、Phe(4-NH₂)、Phe(4-Br)、Phe(4-CN)、Phe(4-CO₂H), Phe (4- (2- amino ethoxies Base)) or Phe (4- guanidine radicals).In certain embodiments, X11 is 2-Nal or 1-Nal.In certain embodiments, X1, X2 and X3 is not present.In certain embodiments, X4 Abu and X9 are Cys.

In certain embodiments, the present invention includes 8 to 20,8 to 16 or 8 to 12 amino acid being optionally cyclized Peptide it includes the core sequence of formula III b or is made from it：

Xaa4-Xaa5-Xaa6-Trp-Xaa8-Xaa9-Xaa10-Xaa11(IIIb)

Wherein Xaa4 and Xaa9 is each independently selected from Abu and Cys, and wherein both Xaa4 and Xaa9 is differed；Xaa5、 Xaa6 and Xaa8 is arbitrary amino acid residue；Xaa10 is Tyr, Phe analog or 2-Nal and Xaa11 is 2-Nal or Trp, The wherein described peptide inhibits the combination of IL-23 and IL-23R.In a particular embodiment, Xaa10 be Phe (4-OMe), 2-Nal or Phe [4- (2- amino ethoxies)].In one embodiment, Xaa10 is Phe (4-OMe).In one embodiment, Xaa7 is Phe [4- (2- amino ethoxies)].In one embodiment, Xaa11 2-Nal.In certain embodiments, peptide It is cyclized via Xaa4 and Xaa9.In a particular embodiment, Phe analogs are Phe [4- (2 amino ethoxy)] or Phe (4- OMe).In certain embodiments, Xaa4 Abu and Xaa9 are Cys, and peptide is cyclized via Xaa4 and Xaa9.Specific In embodiment, the peptide is the inhibitor peptides of formula III, and wherein in certain embodiments, X1, X2 and X3 are not present. In a particular embodiment, the peptide inhibits the combination of IL-23 and IL-23R.In certain embodiments, the peptide packet of formula III b Containing the Glu combined with Xaa4, (D) Glu, Arg, (D) Arg, Phe, (D) Phe, 2-Nal, Thr, Leu or (D) Gln.In certain realities It applies in scheme, is (D) Arg or (D) Phe.

In certain embodiments, the present invention includes 8 to 20,8 to 16 or 8 to 12 amino acid being optionally cyclized Peptide it includes the core sequence of formula III c or is made from it：

Abu-Xaa5-Xaa6-Trp-Xaa8-Cys-[Phe(4-OMe)]-(2-Nal)(IIIc)

Wherein Xaa5, Xaa6 and Xaa8 are arbitrary amino acid residue；And the wherein described peptide inhibits IL-23's and IL-23R In conjunction with.In certain embodiments, the peptide is cyclized via the Cys of the Abu and Xaa9 of Xaa4.In certain embodiments, institute The inhibitor peptides that peptide is formula III are stated, and wherein in certain embodiments, X1, X2 and X3 are not present.In specific embodiment In, the peptide inhibits the combination of IL-23 and IL-23R.In certain embodiments, the peptide of formula III c includes to be combined with Abu Glu, (D) Glu, Arg, (D) Arg, Phe, (D) Phe, 2-Nal, Thr, Leu or (D) Gln.In certain embodiments, it is (D) Arg or (D) Phe.

In certain embodiments, the present invention includes 8 to 20,8 to 16 or 8 to 12 amino acid being optionally cyclized Peptide it includes the core sequence of formula III d or is made from it：

Abu-Xaa5-Xaa6-Trp-Xaa8-Cys-Xaa10-Trp(IIId)

Wherein Xaa5, Xaa6 and Xaa8 are arbitrary amino acid residue；Xaa10 is the Phe of modification；And the wherein described peptide suppression The combination of IL-23 and IL-23R processed.In a particular embodiment, the Phe of modification is Phe (4-tBu), Phe (4- guanidine radicals), Phe [4- (2- amino ethoxies)], Phe (4-CO₂H)、Phe(4-CN)、Phe(4-Br)、Phe(4-NH₂)、PHe(CONH₂) or Phe (4-Me).In a particular embodiment, the Phe of modification is Phe (4-tBu), Phe (4- guanidine radicals), Phe [4- (2- amino ethoxies Base)], Phe (4-CO₂H)、Phe(4-CN)、Phe(4-Br)、Phe(4-NH₂) or Phe (4-Me).In one embodiment, Xaa10 is Phe [4- (2- amino ethoxies)] or Phe (4-OMe).In one embodiment, Xaa10 is Phe [4- (2- ammonia Base oxethyl)].In certain embodiments, the peptide is cyclized via the Cys of the Abu and Xaa9 of Xaa4.In certain embodiments In, the peptide is the inhibitor peptides of formula III, and wherein in certain embodiments, X1, X2 and X3 are not present.Specific real It applies in scheme, the peptide inhibits the combination of IL-23 and IL-23R.In certain embodiments, the peptide of formula III d includes to be tied with Abu The Glu of conjunction, (D) Glu, Arg, (D) Arg, Phe, (D) Phe, 2-Nal, Thr, Leu or (D) Gln.In certain embodiments, It is (D) Arg or (D) Phe.

In certain embodiments, the present invention includes optional 8 to 20 be optionally cyclized, 8 to 16 or 8 to 12 amino The peptide of acid, it includes the core sequence of formula III e or is made from it：

Abu-Xaa5-Xaa6-Trp-Xaa8-Cys-Phe [4- (2- amino ethoxies)]-[2-Nal] (IIIe)

Wherein Xaa5, Xaa6 and Xaa8 are arbitrary amino acid residue.In certain embodiments, the peptide is via Xaa4's The Cys of Abu and Xaa9 is cyclized.In certain embodiments, peptide is the inhibitor peptides of formula III, and wherein in certain embodiment party In case, X1, X2 and X3 are not present.In a particular embodiment, the peptide inhibits the combination of IL-23 and IL-23R.In certain realities Apply in scheme, the peptide of formula III b include the Glu combined with Abu, (D) Glu, Arg, (D) Arg, Phe, (D) Phe, 2-Nal, Thr, Leu or (D) Gln.In certain embodiments, it is (D) Arg or (D) Phe.

In one embodiment, Xaa5 and Xaa8 is Gln.In one embodiment, Xaa6 Thr.In certain realities It applies in scheme, the peptide is cyclized via the Cys of the Abu and Xaa9 of Xaa4.

In the specific embodiment of the inhibitor peptides of formula III, inhibitor peptides have to be tied shown in any table 5A-5C Structure is included in amino acid sequence shown in table 5A-5C.

In some aspects, the present invention provides the inhibitor peptides or its pharmaceutically acceptable salt of Interleukin-23 receptor Or solvate, wherein the inhibitor peptides include the amino acid sequence of formula (Vf)：

X1-X2-X3-Abu-X5-X6-X7-X8-Cys-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19- X20 (Vf),

Wherein：

X1 is not present；

X2 is not present or X2 is D-Asp, E, R, D-Arg, F, D-Phe, 2-Nal, T, L, D-Gln or D-Asn；

X3 is D-Arg；

X5 is N, Q, Cit, Lys or Lys conjugate (for example, Lys (IVA), Lys (biotin), Lys (octyl), Lys (Palm)、Lys(PEG)、Lys(PEG8)、Lys(PEG11-Palm)、Lys(Ac))；

X6 is T, S or V；

X7 is W, 1-Nal or 2-Nal；

X8 is Q, Cit, N, Aib or Lys (Ac)；

X10 is Phe [4- (2- amino ethoxies)], Phe [4- (2- acetyl-aminos ethyoxyl)] or Phe (4-CONH₂)。

X11 is 2-Nal；

X12 is 4- amino -4- carboxyls-oxinane, Aib, α MeLeu, α MeLys or α MeLys conjugates (such as α MeLys (Ac), α MeLys (PEG4-Palm), α MeLys (PEG4- lauryls), α MeLys (the different Glupalm of PEG4), α MeLys (the different Glu lauryls of PEG4), α MeLys (IVA), α MeLys (biotin) or α MeLys (octyl))；

X13 is that (such as Lys (Ac), Lys (the different Glu-Palm of PEG4-), (PEG4- is pungent by Lys for Q, E, Cit or Lys conjugate Base), Lys (PEG4-Palm), Lys (biotin), Lys (octyl), Lys (Palm), Pys (PEG8) or Lys (PEG11- Palm))；

X14 be N, Cit, Q, L, G, S, Aib, F, 2-Nap, N-Me-Ala, R, W, nLeu, Tic or Lys conjugate (such as Lys(Ac))；

X15 is N, Cit, Q, β Ala, Lys (Ac) or Aib；And

X16, X17, X18, X19 and X20 are not present.

In a particular embodiment, X2 D-Asp, E, R, D-Arg, F, D-Phe, 2-Nal, T, L, D-Gln or D-Asn.

In some aspects, the present invention provides the inhibitor peptides or its pharmaceutically acceptable salt of Interleukin-23 receptor Or solvate, wherein the inhibitor peptides include the amino acid sequence of formula (Vh)：

X1-X2-X3-Abu-X5-X6-X7-X8-Cys-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19- X20 (Vh),

Wherein：

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary D- amino acid or is not present；

X5 is Ala, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N- MeArg, Orn, Gln, Arg, Ser, Glu or Thr；

X6 is Thr, Ser, Asp, Ile or arbitrary amino acid；

X7 is Trp, 6- chloro- Trp, 1-Nap or 2-Nap；

X10 is 2-Nal, Phe analog, Tyr or Tyr analogs；

X11 is 1-Nal, 2-Nal, Phe (3,4- dimethoxy), 5- hydroxyls Trp, Phe (3,4-Cl2), Trp or Tyr (3- tBu)。

X12 be Aib, 4- amino -4- carboxyls-oxinane, arbitrary Alpha-Methyl amino acid, α-ethyl-amino acid, Achc, Acvc, Acbc Acpc, 4- amino -4- Carboxy-piperidins, 3-Pal, Agp, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-MeLeu、α-MeOrn、α-MeSer、α-MeVal、Cav、Cha、Cit、Cpa、D-Asn、Glu、His、hLeu、hArg、Lys、 Leu, Octgly, Orn, piperidines, Arg, Ser, Thr or THP；

X13 is Lys (Ac), Gln, Cit, Glu or arbitrary amino acid；

X14 be Asn, Gln, Lys (Ac), Cit, Cav, Lys (N- ε-(N- α-palmityl-L- γ-glutamyls)), Lys (N- ε-palmityl), Asp or arbitrary amino acid；

X15 is β-Ala, Asn, Gly, Gln, Ala, Ser, Aib, Asp or Cit；

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present.

In certain embodiment party of arbitrary inhibitor peptides (including but not limited to those of formula (If) and (Ih)) as described herein In case, inhibitor peptides are cyclized via the key (such as thioether bond) between X4 and X9.In certain embodiments, inhibitor peptides inhibit The combination of Interleukin-23 (IL-23) and IL-23 receptor.

In certain embodiments, X1, X2 and X3 are not present.In certain embodiments, X1 and X2 are not present.Certain In embodiment, X1 is D- amino acid or is not present.In certain embodiments, X2 is D- amino acid or is not present.

In certain embodiments, X5 Ala, α-MeOrn, α-MeSer, Cit, Dap, Dab, Dap (Ac), Gly, Lys, Asn, N-MeGln, N-MeArg, Orn, Gln, Arg, Ser or Thr；

In certain embodiments, X5 N, X6 T, X7 are W or X8 is Q.In certain embodiments, X5 N, X6 are T, X7 are W and X8 is Q.

In certain embodiments, X5 Q, X6 T, X7 are W or X8 is Q.In certain embodiments, X5 Q, X6 are T, X7 are W and X8 is Q.

In certain embodiments, X5 N, X6 T, X7 are W and X8 is Cit.

In certain embodiments, X10 is Phe [4- (2- amino ethoxies)].

In certain embodiments, X12 is 4- amino -4- carboxyls-oxinane, Aib, α MeLeu or α MeLys.At certain In a little embodiments, X12 is 4- amino -4- carboxyls-oxinane.

In certain embodiments, X13 is E or Lys (Ac).In certain embodiments, X13 is Lys (Ac).

In certain embodiments, X14 Asn, Gln, Lys (Ac), Cit, Cav, Lys (N- ε-(N- α-palmityl- L- γ-glutamyls)), Lys (N- ε-palmityl) or arbitrary amino acid；

In certain embodiments, X15 is β-Ala, Asn, Gly, Gln, Ala, Ser, Aib or Cit.

In certain embodiments, X14 N.

In certain embodiments, X15 N.

In certain embodiments, X2 is not present；X3 is not present；X5 is that Q, X6 T, X7 W, and X8 are Q；X10 is Phe [4- (2- amino ethoxies)]；X12 is 4- amino -4- carboxyls-oxinane, Aib, α MeLeu or α MeLys；X13 is E or Lys (Ac)；X14 is N；And X15 is N.In certain embodiments, X12 is 4- amino -4- carboxyls-oxinane and X13 is Lys(Ac)。

In certain embodiments, the arbitrary amino acid of inhibitor peptides is connected by junction portion (such as PEG).

In certain embodiments, the N-terminal of inhibitor peptides includes Ac groups.

In certain embodiments, the C-terminal of inhibitor peptides includes NH₂Group.

In certain embodiments, the present invention include amino acid sequence shown in any of table 4s or table 5s or by Its peptide formed, or include structure shown in any of table 4s or table 5s or the inhibitor peptides being made from it (or its Pharmaceutically acceptable salt).In a particular embodiment, the peptide does not include conjugated part, but includes Abu residues.Specific In embodiment, the peptide or inhibitor two in the bracket between two Abu and Cys residues or after term " ring " is most Include thioether bond between the amino acid of outside, this shows that there are cyclic structures.In a particular embodiment, inhibitor is acetate. The peptide sequence of exemplary inhibitor is shown in from N-terminal to C-terminal in table 4 and table 5, has conjugated part, and indicate N-terminal Ac And/or C-terminal NH₂Group.As shown in table 5, cyclic structure is indicated by " ring ", show Cys at the Abu and X9 that are included at X4 it Between there are thioether bonds.

4. exemplary thioether inhibitor peptides of table

The exemplary thioether inhibitor peptides of table 5A.

Ac- rings-[[Abu]-XXWXC]-[Phe (4-OMe)]-[2-Nal]-XXXX-NH₂

The exemplary thioether peptides of table 5B.

Ac- [D-Arg]-ring-[Abu-QTWQC]-[Phe (4-2ae)]-[2-Nal]-[THP]-ENN-NH₂
	Ac- [D-Arg]-ring-[Abu-QTWQC]-[Phe (4-2ae)]-[2-Nal]-[THP]]-END-NH₂
Ac- [D-Arg]-ring-[Abu-QTWQC]-[Phe (4-2ae)]-[2-Nal]-[THP]-EDN-NH₂
	Ac- [D-Arg]-ring-[Abu-QTWEC]-[Phe (4-2ae)]-[2-Nal]-[THP]-ENN-NH₂
Ac- [D-Arg]-ring-[Abu-ETWQC]-[Phe (4-2ae)]-[2-Nal]-[THP]-ENN-NH₂
	Ac- [D-Arg]-ring-[Abu-QTWQC]-[Phe (4-2ae)]-[2-Nal]-[THP]-EDD-NH₂
Ac- [D-Arg]-ring-[Abu-QTWEC]-[Phe (4-2ae)]-[2-Nal]-[THP]-END-NH₂
	Ac- [D-Arg]-ring-[Abu-ETWQC]-[Phe (4-2ae)]-[2-Nal]-[oxinane-A]-END-NH₂
Ac- [D-Arg]-ring-[Abu-QTWEC]-[Phe (4-2ae)]-[2-Nal]-[THP]-EDN-NH₂
	Ac- [D-Arg]-ring-[Abu-ETWQC]-[Phe (4-2ae)]-[2-Nal]-[oxinane-A]-EDN-NH₂
Ac- [D-Arg]-ring-[Abu-ETWEC]-[Phe (4-2ae)]-[2-Nal]-[THP]-ENN-NH₂
	Ac- [D-Arg]-ring-[Abu-QTWQC]-[Phe (4-2ae)]-[2-Nal]-[THP]-ENN-NH₂
Ac- [D-Arg]-ring-[Abu-QTWQC]-[Phe (4-2ae)]-[2-Nal]-[THP]-END-NH₂
	Ac- [D-Arg]-ring-[Abu-QTWQC]-[Phe (4-2ae)]-[2-Nal]-[oxinane-A]-EDN-NH₂
Ac- [D-Arg]-ring-[Abu-ETWEC]-[Phe (4-2ae)]-[2-Nal]-[THP]-ENN-NH₂
	Ac- [D-Arg]-ring-[Abu-ETWQC]-[Phe (4-2ae)]-[2-Nal]-[oxinane-A]-ENN-OH

Exemplary peptides inhibitor containing cyclic amides

In certain embodiments, the present invention, which includes the inhibitor peptides of Interleukin-23 receptor or its pharmacy, to connect The salt or solvate received, wherein inhibitor peptides have the structure of formula IV：

R¹-X-R²(IV)

Wherein R¹For key, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, C1-C20 hydrocarbon acyl groups, And including any one of aforementioned individual PEGylated forms or as the PEGylated forms of introns；

R²For key, OH or NH₂；And

X is the amino acid sequence of 8 to 20 amino acid, it includes the sequence of formula IV a or is made from it：

X1-X2-X3-X4-X5-X6-W-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (IVa)

Wherein

X1 is not present or is arbitrary amino acid；

X2 is not present or is arbitrary amino acid；

X3 is not present or is arbitrary amino acid；

X4 is Dap, Dab, Glu, Asp, (D)-Asp or (D)-Dab；

X5 be Gln, Ala, Cys, Cit, Asp, Dab, Dap, Glu, Phe, Gly, His, hCys, Lys, Leu, Met, Asn, N-Me-Ala, N-M-Asn, N-Me-Lys, N-Me-Gln, N-Me-Arg, Orn, Pro, Pen, Gln, Arg, Ser, Thr or Val；

X6 is Thr, Asp, Glu, Phe, Asn, Pro, Arg, Ser or Thr；

X7 is Trp, Glu, Gly, Ile, Asn, Pro, Arg, Thr or OctGly；

X8 is Gln, Glu, Phe, Lys, Asn, Pro, Arg, Thr or Trp；

X9 is Dap, Dab, Glu, Asp, (D)-Asp or (D)-Dab；

X10 be Tyr (OMe) Phe (4-OMe), 1-Nal, 2-Nal, Aic, a-MePhe, Bip, (D) Cys, Cha, DMT, (D) Tyr), Glu, Phe, His, hPhe (3,4- dimethoxy), hTyr, N-Me-Tyr, Trp, Phe (4-CONH₂)、Phe(4- Phenoxy group), Thr, Tic, Tyr, Tyr (3-tBu), Phe (4-tBu), Phe (4-CN), Phe (4-Br), Phe (4-NH₂)、Phe (4-F), Phe (3,5-F₂), Phe (5-F), Phe (3,4-Cl₂)、Phe(4-CF₃), Bip, Cha, 4- pyriylalanine, β hTyr、OctGly、Phe(4-N₃), Phe (4-Br) or Phe [4- (2- amino ethoxies)]；

X11 is 2-Nal, 1-Nal, 2,4- dimethyl Phe, Bip, Phe (3,4-Cl₂), Phe (3,5-F₂)、Phe(4- CONH₂), Phe (4-F), 4- phenylcyclohexyls alanine, Phe (4-CF₃)、α-MePhe、βhPhe、βhTyr、βhTrp、BIP、 Nva (5- phenyl), Phe, His, hPhe, Tic, Tqa, Trp, Tyr, Phe (4-OMe), Phe (4-Me), Trp (2,5,7- tri--uncles Butyl), Phe (4-O allyls), Tyr (3-tBu), Phe (4-tBu), Phe (4- guanidine radicals), Tyr (Bzl) or OctGly；

X12 be α-MeLys, α-MeOrn, α-MeLeu, Aib, (D) Ala, (D) Asn, (D) Leu, (D) Asp, (D) Phe, (D) Thr, 3-Pal, Aib, β-Ala, β-Glu, β hAla, β hLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu, Asn, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr, Tle, 4- amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, α-diethyl Gly、α-MeLys、α-MeLys(Ac)、α-Me-Leu、α-MeSer、α-MeVal；

X13 is Lys (Ac), (D) Asn, (D) Leu, (D) Thr, (D) Phe, Ala, Aib, α-MeLeu, Aib, β-Ala, β- Glu, β hAla, β hLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, Lys, Lys (Ac), Leu, Asn, Ogl, Pro, Gln, Arg, Ser, β-spiral shell-pip, Thr, Tba, Tlc, Val or Tyr；

X14 be Asn, Glu, Phe, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr；

X15 be β-ala, Asn, Gly, (D) Ala, (D) Asn, (D) Asp, (D) Leu, (D) Phe, (D) Thr, Ala, AEA, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg or Ser；

X16 is not present, and is Gly, Ala, Asp, Ser, Pro, Asn or Thr；

X17 is not present, and is Glu, Ser, Gly or Gln；

X18 is not present or is arbitrary amino acid；

X19 is not present or is arbitrary amino acid；And

X20 is not present or is arbitrary amino acid.

In certain embodiments of Iva：X12 be α-MeLys, α-MeOrn, α-MeLeu, Aib, (D) Ala, (D) Asn, (D) Leu, (D) Asp, (D) Phe, (D) Thr, 3-Pal, Aib, β-Ala, β-Glu, β hAla, β hLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeu, hArg, hLeu, Ile, Lys, Leu, Asn, N- MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Arg, Ser, Thr or Tle；X13 is Lys (Ac), (D) Asn, (D) Leu, (D) Thr, (D) Phe, Ala, Aib, α-MeLeu, Aib, β-Ala, β-Glu, β hAla, β hLeu, β hVal, β-spiral shell-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, Glu, Phe, hLeuLys, Leu, Asn, Ogl, Pro, Gln, Arg, Ser, β-spiral shell- Pip, Thr, Tba, Tlc, Val or Tyr；X14 be Asn, Glu, Phe, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic or Tyr；And X15 be Gly, (D) Ala, (D) Asn, (D) Asp, (D) Leu, (D) Phe, (D) Thr, Ala, AEA, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Gln, Arg or Ser.

In the specific embodiment of the inhibitor peptides of formula (IV)：X5 be Cys, Cit, Asp, Dab, Dap, Gly, His, hCys、Lys、Met、Asn、N-Me-Ala、N-Me-Asn、N-Me-Lys、N-Me-Gln、N-Me-Arg、Orn、Pro、Pen、 Gln、Val；X6 is Glu, Arg, Ser；X7 is Trp, Glu, Gly, Ile, Asn, Pro, Arg, Thr or OctGly；X8 be Phe, Asn、Pro、Arg、Thr、Trp；X10 be Phe (4-OMe), 1-Nal, 2-Nal, Aic, α-MePhe, Bip, (D) Cys, Cha, DMT, (D) Tyr, Glu, His, hPhe (3,4- dimethoxy), hTyr, N-Me-Tyr, Trp, Phe (4-CONH₂)、Phe-(4- Phenoxy group), Thr, Tic, Tyr (3-tBu), Phe (4-tBu), Phe (4-CN), Phe (4-Br), Phe (4-NH₂)、Phe(4- F), (3,5-F Phe₂)、PheCH₂CO₂H, Phe (5-F), Phe (3,4-Cl₂)、Phe(4-CF₃), the third ammonia of Bip, Cha, 4- pyridyl group Acid, β hTyr, OctgGly, Tyr (4-N₃), Phe (4-Br), Phe [4- (2- amino ethoxies)]；X11 be 2-Nal, 1-Nal, 2,4- dimethyl Phe, Bip, Phe (3,4-Cl₂), Phe (3,5-F₂)、Phe(4-CONH₂), Phe (4-F), 4- phenylcyclohexyls, Phe(4-CF₃), α-MePhe, Nal, β hPhe, β hTyr, β hTrp, BIP, Nva (5- phenyl), Phe, His, hPhe, Tic, Tqa, Tyr, Phe (4-OMe), Phe (4-Me), Tyr (2,5,7- tri--tertiary butyl), Phe (4-O allyls), Phe (3-tBu), Phe (4-tBu), Phe (4- guanidine radicals), Tyr (Bzl), OctGly；X12 is α-Me-Lys, D-Ala, (D) Asn, (D) Asp, (D) Leu, (D) Phe, (D) Tyr, Aib, α-MeLeu, α-MeOrn, Aib, β-Ala, β hAla, β hArg, β hLeu, β hVal, β-spiral shell- Pip, Glu, hArg, Ile, Lys, N-MeLeu, N-MeArg, Ogl, Orn, Pro, Gln, Ser, Thr, Tle, 4- amino -4- carboxylics Base-oxinane, Achc, Acpc, Acbc, Acvc, α-diethyl Gly, α-MeLys (Ac), α-MeSer, α-MeVal；X13 is Lys、Lys(Ac)、(D)Asn、(D)Leu、(D)Phe、(D)Thr、Ala、α-MeLeu、Aib、β-Ala、β-Glu、βhLeu、β HVal, β-spiral shell-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, hLeu, Asn, Ogl, Pro, Gln, Ser, Thr, Tba、Tle；X14 is Glu, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic；X15 be (D) Ala, (D) Asn, (D) Asp, (D) Leu, (D) Phe, (D) Thr, Aea, Asp, Glu, Phe, Gly, Lys, Leu, Pro, Asn, Arg or β-Ala；X16 is Gly, Ser, Pro, Asn, Thr；Or X17 is Glu, Ser, Gly, Gln.

In the specific embodiment of the inhibitor peptides of formula (IV)：X5 be Cys, Cit, Asp, Dab, Dap, Gly, His, hCys、Lys、Met、Asn、N-Me-Ala、N-Me-Asn、N-Me-Lys、N-Me-Gln、N-Me-Arg、Orn、Pro、Pen、 Gln、Val；X6 is Glu, Arg, Ser；X7 is Trp, Glu, Gly, Ile, Asn, Pro, Arg, Thr or OctGly；X8 be Phe, Asn、Pro、Arg、Thr、Trp；X10 be Phe (4-OMe), 1-Nal, 2-Nal, Aic, α-MePhe, Bip, (D) Cys, Cha, DMT, (D) Tyr, Glu, His, hPhe (3,4- dimethoxy), hTyr, N-Me-Tyr, Trp, Phe (4-CONH₂)、Phe-(4- Phenoxy group), Thr, Tic, Tyr (3-tBu), Phe (4-tBu), Phe (4-CN), Phe (4-Br), Phe (4-NH₂)、Phe(4- F), (3,5-F Phe₂)、PheCH₂CO₂H, Phe (5-F), Phe (3,4-Cl₂)、Phe(4-CF₃), the third ammonia of Bip, Cha, 4- pyridyl group Acid, β hTyr, OctgGly, Tyr (4-N₃), Phe (4-Br), Phe [4- (2- amino ethoxies)]；X11 be 2-Nal, 1-Nal, 2,4- dimethyl Phe, Bip, Phe (3,4-Cl₂), Phe (3,5-F₂)、Phe(4-CONH₂), Phe (4-F), 4- phenylcyclohexyls, Phe(4-CF₃), α-MePhe, Nal, β hPhe, β hTyr, β hTrp, BIP, Nva (5- phenyl), Phe, His, hPhe, Tic, Tqa, Tyr, Phe (4-OMe), Phe (4-Me), Tyr (2,5,7- tri--tertiary butyl), Phe (4-O allyls), Phe (3-tBu), Phe (4-tBu), Phe (4- guanidine radicals), Tyr (Bzl), OctGly；X12 is α-Me-Lys, D-Ala, (D) Asn, (D) Asp, (D) Leu, (D) Phe, (D) Tyr, Aib, α-MeLeu, α-MeOrn, Aib, β-Ala, β hAla, β hArg, β hLeu, β hVal, β-spiral shell- pip、Glu、hArg、Ile、Lys、N-MeLeu、N-MeArg、Ogl、Orn、Pro、Gln、Ser、Thr、Tle；X13 is Lys (Ac)、(D)Asn、(D)Leu、(D)Phe、(D)Thr、Ala、α-MeLeu、Aib、β-Ala、β-Glu、βhLeu、βhVal、β- Spiral shell-pip, Cha, Chg, Asp, Dab, Dap, α-diethyl Gly, hLeu, Asn, Ogl, Pro, Gln, Ser, Thr, Tba, Tle； X14 is Glu, Gly, His, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Tic；X15 be (D) Ala, (D) Asn, (D)Asp、(D)Leu、(D)Phe、(D)Thr、Aea、Asp、Glu、Phe、Gly、Lys、Leu、Pro、Arg；X16 be Gly, Ser, Pro、Asn、Thr；Or X17 is Glu, Ser, Gly, Gln.

In certain embodiments, inhibitor peptides are cyclisation.In a particular embodiment, the peptide by X4 and X9 it Between intramolecular bond cyclisation.In a particular embodiment, intramolecular bond is amido bond.

In certain embodiments, inhibitor peptides are linear or are not cyclisation.

In the specific embodiment of the inhibitor peptides of formula IV, one or more of X1, X2 and X3, two or more Or whole three is not present.

In certain embodiments, X3 Glu, (D) Glu, Arg, (D) Arg, Phe, (D) Phe, 2-Nal, Thr, Leu or (D)Gln.In certain embodiments, X3 is (D) Arg or (D) Phe.

In the specific embodiment of the inhibitor peptides of formula IV, one or more of X17, X19 and X20, two or more Multiple or whole three is not present.

In the specific embodiment of the inhibitor peptides of formula IV, X4 Dap, Dab or (D) Dab and X9 are Glu, (D) Asp or Asp.In the specific embodiment of the inhibitor peptides of Formulas I, X4 Glu, (D) Asp or Asp and X9 are Dab, Dap Or (D) Dab.

In the specific embodiment of the inhibitor peptides of formula IV, X18 is (D)-Lys.In certain embodiments, X17 is not In the presence of and X18 be (D)-Lys.

In the specific embodiment of the inhibitor peptides of formula IV, inhibitor peptides include one or more of following characteristics, Two or more, three or more or all four：X5 is Gln；X6 is Thr；X7 is Trp；And X8 is Gln.

In the specific embodiment of the inhibitor peptides of formula IV, inhibitor peptides include one or more of following characteristics, Two or more, three or more, four or more, five or more, six or more or seven：X10 For Tyr, Phe [4- (2- amino ethoxies)], Phe (4-CONH₂) or Phe (4-OMe)；X11 is 2-Nal or Trp；X12 is 4- Amino -4- carboxyls-oxinane, Achc, Acpc, Acbc, Acvc, Aib, α-diethyl Gly, α-MeLys, α-MeLys (Ac), α-Me-Leu, α-MeOrn, α-MeSer, α-MeVal or Arg；X13 is Glu or Lys (Ac)；X14 is Asn；X15 is Gly, Asn Or β-Ala；And X16 is AEA.In the specific embodiment of the inhibitor peptides of formula IV, inhibitor peptides include in following characteristics One or more, two or more, three or more, four or more, five or more, six or more Or seven：X10 is Tyr；X11 is Trp；X12 is Arg；X13 is Glu；X14 is Asn；X15 is Gly；And X16 is AEA.

In the specific embodiment of the inhibitor peptides of formula IV, inhibitor peptides include one or more of following characteristics, Two or more, three or more, four or more, five or more, six or more, seven or more A, eight or more, nine or more, ten or more or whole：X5 is Gln；X6 is Thr；X7 is Trp；X8 For Gln；X10 is Tyr；X11 is Trp；X12 is Arg；X13 is Glu or Lys (Ac)；X14 is Asn；X15 is Gly；And X16 For AEA.In the specific embodiment of the inhibitor peptides of formula IV, inhibitor peptides include one or more of following characteristics, two It is a or more, three or more, four or more, five or more, six or more, seven or more, Eight or more, nine or more, ten or more or whole：X5 is Gln；X6 is Thr；X7 is Trp；X8 is Gln；X10 is Tyr；X11 is Trp；X12 is Arg；X13 is Glu；X14 is Asn；X15 is Gly；And X16 is AEA.

In certain embodiments of the inhibitor peptides of formula IV, the peptide is cyclized via X4 and X9；X5, X6, X7 and X8 points It Wei not Gln, Thr, Trp and Gln；And X10, X11, X12, X13, X14, X15 and X16 be respectively Tyr, Trp, Arg, Glu, Asn, Gly and AEA.

In certain embodiments, the present invention includes the peptide for 8 to 20 amino acid being optionally cyclized, and it includes core sequences Or be made from it, the core sequence includes：

Xaa4-Xaa5-Xaa6-Trp-Xaa8-Xaa9- [Phe (4-OMe)]-[2-Nal] (formula IV b)

Wherein Xaa4 and Xaa9 is each independently selected from Dap, Dab, Glu, Asp, (D)-Asp and (D)-Dab, wherein Xaa4 Intramolecular bond can be formed with Xaa9, for example, cyclic amides；And Xaa5, Xaa6 and Xaa8 are arbitrary amino acid residue, wherein institute State the combination that peptide inhibits IL-23 and IL-23R.In a particular embodiment, inhibitor peptides are the inhibitor peptides of formula IV.Specific In embodiment, the peptide inhibits the combination of IL-23 and IL-23R.

In certain embodiments of the inhibitor peptides of formula IV, inhibitor peptides have table 7 shown in structure or comprising Amino acid sequence shown in table 7.

Certain exemplary peptides inhibitor of the present invention are also depicted in formula (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg) In any of (Vh) and table 2-5, the formula and table provide the amino acid sequence of selected inhibitor peptides.These peptides press down Preparation is acetate.

The optional feature of inhibitor peptides

Any inhibitor peptides of the present invention can be with for example, be further limited as described below.It should be understood that can will herein Each described further limited in feature is applied to arbitrary inhibitor peptides, wherein the amino acid specified in specific position Allow to exist and further limits feature.

In certain embodiments of any inhibitor peptides described herein, inhibitor peptides are cyclisation.

In certain embodiments of any inhibitor peptides described herein, inhibitor peptides or monomer subunit are linear Or be not cyclisation.In the wherein described peptide is certain embodiments that are linear or not being cyclisation, X4 and X9 can be with For arbitrary amino acid.

In certain embodiments, inhibitor peptides are for example cyclized by X4 and X9.

In different implementation scenarios, R¹For key, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 hydrocarbon Base or C1-C20 hydrocarbon acyl groups, and include any one of aforementioned (such as acetyl group) individually PEGylated forms or as Every the PEGylated forms of son.It should be understood that other than the typical amido of the aminoterminal positioned at peptide, R¹It can replace or deposit .It should also be understood that R¹It can be not present.In certain embodiments, inhibitor peptides include the ends N- selected from the following：Hydrogen, C1-C6 Alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl or C1-C20 hydrocarbon acyl groups, and include it is any one of aforementioned (such as Acetyl group) individually PEGylated forms or the PEGylated forms as introns.In any peptide described herein In the specific embodiment of inhibitor, R¹Or N-terminal portion is hydrogen.In certain embodiments, R¹For key, for example, covalent bond.

With it is shown in this article it is various in any inhibitor peptides of any one certain embodiments in, R¹Or N-terminal portion It is selected from methyl, acetyl group, formoxyl, benzoyl, trifluoroacetyl group, isovaleryl, isobutyryl, octyl (octanyl), And the conjugated amide of lauric acid/dodecanoic acid, hexadecylic acid and γ-Glu- hexadecylic acids.In one embodiment, R¹Or N-terminal portion is pGlu.In certain embodiments, R¹For hydrogen.In a particular embodiment, R¹For acetyl group, thus inhibitor peptides are at its end N- It is acylated, for example, to cap or protect n terminal amino acid residue, for example, the ends N- Pen or Abu residues.

In certain embodiments of any inhibitor peptides described herein, R¹Or N-terminal portion is acid.In certain implementations In scheme, R¹Or N-terminal portion is acid selected from the following：It is acetic acid, formic acid, benzoic acid, trifluoroacetic acid, isovaleric acid, isobutyric acid, pungent Acid, lauric acid/dodecanoic acid, hexadecylic acid, biphenylacetic acid, 4- fluorophenylacetic acids, gallic acid, pyroglutamic acid, cyclopentyl propionic acid, glycolic, grass Acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzene first Acid, 3- (4- hydroxy benzoyls) benzoic acid, cinnamic acid, mandelic acid, 4- methyl bicyclics (2.2.2)-oct-2-ene -1- carboxylic acids, Portugal Heptonic acid, 3- phenylpropionic acids, trimethylace tonitric, butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, water Poplar acid, stearic acid, muconic acid, hydrocarbyl sulfonic and aryl sulfonic acid.

In a particular embodiment, R¹Or N-terminal portion is selected from methanesulfonic acid, ethanesulfonic acid, 1,2- ethane-disulfonic acid and 2- hydroxyls The hydrocarbyl sulfonic of base ethanesulfonic acid.

In a particular embodiment, R¹Or N-terminal portion is selected from benzene sulfonic acid, 4- chlorobenzenesulfonic acids, 2- naphthalene sulfonic acids, 4- toluene sulphurs The aryl sulfonic acid of acid and camphorsulfonic acid.

In some embodiments, wherein the present invention peptide include with acid compound such as, for example, isovaleric acid, isobutyric acid, Valeric acid etc. is conjugated, and such conjugated presence is mentioned as the acid.Thus, for example, but do not limit in any way, In some embodiments, the application refers to such be conjugated for isovaleric acid-[Pen]-QTWQ [Pen]-[Phe (4-OMe)]- [2-Nal]-[α-MeLys]-[Lys(Ac)]-NG-NH₂Instead of indicating the conjugated of isovaleric acid and peptide by the isovaleryl that refers to, For example, isovaleryl-[Pen]-QTWQ [Pen]-[Phe (4-OMe)]-[2-Nal]-[α-MeLys]-[Lys (Ac)]-NG- NH₂.Referred in the form of its acid it is conjugated be intended to cover be present in inhibitor peptides in the form of.

In certain embodiments, inhibitor peptides include to be selected from key, OH or NH₂The ends C- (for example, R²Or C-terminal part). In certain embodiments, R²For key.With it is shown in this article it is various in any inhibitor peptides of any one different embodiment party In case, R²Or C-terminal part is OH or NH₂.It should be understood that in addition to being usually located at the carboxyl of c-terminus of peptide, R²Or C-terminal part can To replace or exist.It should also be understood that R²It can be not present.

With it is shown in this article it is various in any inhibitor peptides of any one specific embodiment in, X include it is following Or it is made up of：7 to 35 amino acid residues, 8 to 35 amino acid residues, 9 to 35 amino acid residues, 10 to 35 ammonia Base acid residue, 7 to 25 amino acid residues, 8 to 25 amino acid residues, 9 to 25 amino acid residues, 10 to 25 amino acid Residue, 7 to 20 amino acid residues, 8 to 20 amino acid residues, 9 to 20 amino acid residues, 7 to 18 amino acid residues, 8 to 18 amino acid residues, 9 to 18 amino acid residues or 10 to 18 amino acid residues.

In certain embodiments of any formula shown in this article, either one or two X is not included in U.S. Patent application Amino acid sequence shown in disclosing No. US2013/0029907 is not made from it.In certain of any formula shown in this article In a little embodiments, either one or two X is not included in shown in U.S. Patent Application Publication No. US2013/0172272 Amino acid sequence is not made from it.

In certain embodiments of any inhibitor peptides described herein, inhibitor peptides or its each monomelic subunit include Below or it is made up of：At least three, at least four, at least five, at least six or at least 7 of the c-terminus of X9 amino acid residues A amino acid residue.In the specific embodiment of any inhibitor peptides described herein, inhibitor peptides include X9 amino acid 3 to 11 of the c-terminus of residue, 3 to 10,3 to 9,3 to 8,3 to 7,3 to 6,3 to 5,3 to 4,3,4 A, 5,6,7,8,9,10 or 11 amino acid residues.

In certain embodiments of any inhibitor peptides described herein, inhibitor peptides or its each monomelic subunit include 4 amino acid residues between X4 and X9 are made from it.In one embodiment, X4 and X9 is cysteine.

In certain embodiments, the inhibitor peptides of any formula as described herein are residual comprising the amino acid for being expressed as X4-X15 Base or part.In a particular embodiment, inhibitor peptides do not include X1-X3 or X16-X20.In certain embodiments, described Inhibitor peptides include that the N-terminal for 1 to 3 amino acid residue for corresponding to any of X1-X3 extends.In a particular embodiment, It is D- amino acid in the presence of any of X1, X2 and X3 or multiple.In certain embodiments, the inhibitor peptides packet Include the C-side extension of 1 to 5 amino acid residue corresponding to any of X16-X20.In a particular embodiment, when X16, It is D- amino acid in the presence of any of X17, X18, X19 and X20 or multiple.It is likely to be present in N-terminal and/or C-side extension Exemplary amino acid residues are shown in table 3 and table 5.These tables each illustrate the first inhibitor peptides and it includes N-terminals to extend, C End extends and/or the derivative of conjugation moiety.The present invention includes the derivative of any inhibitor peptides as described herein, and it includes one A or multiple such N- end extensions, the ends C- extend and/or conjugation moiety.In certain embodiments, extension bit in table 3 and table 5 Any amino acid residue shown in setting can be present in the inhibitor peptides of the present invention in any combination.In specific embodiment party In case, such as when being applied to object, N-terminal and/or C-side extension are related to increased half-life period.

In certain embodiments of any inhibitor peptides described herein, inhibitor peptides or its each monomelic subunit include For example, in X7-X11 aa sequence motifs W-X-X-Y-W.In certain embodiments, inhibitor peptides or its each monomer Subunit includes for example, in X4-X11 aa sequence motifs C-X-X-W-X-C-Y-W.In certain embodiments, peptide presses down Preparation or its each monomelic subunit include for example, in X4-X11 aa sequence motifs Pen-X-X-W-X-Pen-Y-W.At this In certain embodiments of any inhibitor peptides described in text, inhibitor peptides or two monomelic subunit do not include and for example exist X7-X11 aa sequence motifs W-X-X-Y-W, wherein X are arbitrary amino acid.

In any formula described herein or certain embodiments of inhibitor peptides, inhibitor peptides include the ends N- of X4 One or more amino acid residues.In a particular embodiment, X3 is existing.In certain embodiments, X3 Glu, (D) Glu, Arg, (D) Arg, Phe, (D) Phe, 2-Nal, Thr, Leu or (D) Gln.In certain embodiments, X3 be (D) Arg or (D)Phe。

In any formula described herein or the specific embodiment of inhibitor peptides, inhibitor peptides are included in the amino of X2 Acid.In a particular embodiment, X2 Glu, (D) Asp, Arg, (D) Arg, Phe, (D) Phe, 2-Nal, Thr, Leu, (D) Gln Or (D) Asn.In certain embodiments, X2 and X3 is existing.In a particular embodiment, X2 Glu, (D) Asp, Arg, (D) Arg, Phe, (D) Phe, 2-Nal, Thr, Leu, (D) Gln or (D) As and X3 are (D) Arg.

In certain embodiments, inhibitor peptides of the invention or one or both monomelic subunit are optionally in its C- End includes one of following amino acid sequence：

ENG；

ENN；

[4- amino -4- carboxyls-oxinane]-ENN；

[Lys(Ac)]-NN；

[α-MeLys]-ENG；

[α-MeLys]-[Lys(Ac)]-NN；

[α-MeLeu]-[Lys(Ac)]-NN；

[α-MeLeu]-ENG；

[α-MeOrn]-[Lys(Ac)]-NG；

[α-MeLeu]-ENG；

Aib-[Lys(Ac)]-NG；

Aib-[Lys(Ac)]-NN；

NG-[AEA]-[(D)-Lys]；

[Dapa]-NG-[AEA]-[(D)-Lys]；

[Orn]-NG-[AEA]-[(D)-Lys]；

[α-MeLys]-ENN；

[4- amino -4- carboxyls-oxinane]-[Lys (Ac)]-NN；

[Achc]-[Lys(Ac)]-NN；Or

[Acpc]-[Lys(Ac)]-NN。

In a particular embodiment, the end C-terminal amino acid of one of these amino acid sequences component peptide.It is being embodied In scheme, these amino acid sequences correspond to X13-X15 or X12-X15 or X14-X16 or X13-X17.

WQCY-[2-Nal]-[α-MeLys]；

WQC-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]；

WQC-[Phe(4-OMe)]-[2-Nal]-[Aib]；

WQ-[Pen]-[Phe(4-OMe)]-[2-Nal]-[α-MeLys]；

W-Xaa8-C-Phe [4- (2- amino ethoxies)]-[2-Nal]；

W-Xaa8-C-Phe [4- (2- amino ethoxies)]-[1-Nal]；

W-Xaa8-C-Phe [4- (2- amino ethoxies)]；Or

W-Xaa8-C-[Phe(4-OCH₃)].In a particular embodiment, the end of one of these amino acid sequences component peptide Hold C-terminal amino acid.In a particular embodiment, these amino acid sequences correspond to X7 to X12 or X7 to X11 or X7 to X10.

In any inhibitor peptides described herein, (including the monomer of peptide monomer inhibitor and peptide dimer inhibitor is sub- Base) certain embodiments in, peptide monomer inhibitor or monomelic subunit are via its n terminal amino acid residue and its C-terminal amino acid Peptide bond cyclisation between residue.In a particular embodiment, inhibitor peptides (or monomer subunit) include point between X4 and X9 Peptide bond between sub- internal key and its n terminal amino acid residue and its C-terminal amino acid residue.In certain embodiments, molecule Internal key is any one of those of described herein, for example, disulfide bond or thioether bond.

X1-X2-X3-Pen-X5-X6-W-X8-Pen-X10-X11-X12-X13-X14-X15；

Pen-X5-X6-W-Q-Pen；

Pen-X5-X6-W-X8-Pen；

Pen-X5-X6-W-X8-Pen-[Phe(4-CONH2)]；And

Pen-X5-X6-W-X8-Pen- [Phe [4- (2- amino ethoxies)]],

Wherein Pen residues are connected by intramolecular bond (for example, disulfide bond).X1、X2、X3、X5、X6、X8、X10、X11、 X12, X13, X14 and X15 can be arbitrary amino acid.In some embodiments, X5 Arg, Asn, Gln, Dap, Orn；X6 For Thr or Ser；And X8 is Gln, Val, Phe, Glu, Lys.In a particular embodiment, X1, X2, X3, X5, X6, X8, As described in this article the defining described in any various and inhibitor peptides of X10, X11, X12, X13, X14 and X15.

X1-X2-X3-Abu-X5-X6-W-X8-C-X9-X10-X11-X12-X13-X14-X15；

Abu-X5-X6-W-Q-C；

Abu-X5-X6-W-X8-C；

Abu-X5-X6-W-X8-C-[Phe(4-CONH2)]；And

Abu-X5-X6-W-X8-C- [Phe [4- (2- amino ethoxies)]],

Wherein Abu and C is keyed by the thioether of intramolecular.X1、X2、X3、X5、X6、X8、X10、X11、X12、X13、 X14 and X15 can be arbitrary amino acid.In some embodiments, X5 Arg, Asn, Gln, Dap, Orn；X6 be Thr or Ser；And X8 is Gln, Val, Phe, Glu, Lys.In a particular embodiment, X1, X2, X3, X5, X6, X8, X10, X11, As described in this article the defining described in any various and inhibitor peptides of X12, X13, X14 and X15.

In certain embodiments, any inhibitor peptides described herein can be via its n terminal amino acid residue and its Peptide bond between C-terminal amino acid residue is further cyclized.In a particular embodiment, inhibitor peptides include X3 or X4 and X9, Peptide bond between any one in X10, X11, X12, X13, X14, X15, X16, X17, X18, X19 or X20.In specific embodiment In, inhibitor peptides of the invention include the peptide bond between its end N- and C-terminal amino acid residue, and they also include X4 and X9 Between intramolecular bond.In certain embodiments, intramolecular bond is disulfide bond, thioether bond, lactam bond or described herein Any other key.

Peptide dimer

In certain embodiments, the present invention includes the dimer of monomer inhibitor peptides described herein comprising this The dimer of any monomer inhibitor peptides described in text or subordinate list, attached drawing or sequence table.These dimers are fallen into be made herein In the range of general terms " inhibitor peptides ".The exemplary dimer of the present invention is also shown graphically in subordinate list, the table in bracket Show Dimerized monomelic subunit, is then connector.Unless otherwise indicated, the subunit is connected through its end C-.Such as in peptide dimerization Term " dimer " in body refers to two connected compounds of peptide monomer subunit.The peptide dimer inhibitor of the present invention can wrap Containing two identical monomelic subunits, homodimer is generated, or can include two different monomelic subunits, generated different Source dimer.Cysteine dimer includes two peptide monomer subunits connected by disulfide bond, and the disulfide bond is in a list Between the cysteine residues in cysteine residues and another monomelic subunit in body subunit.

In some embodiments, inhibitor peptides of the invention are in active when dimer conformation, especially work as trip From cysteine residues be present in peptide when.In certain embodiments, this exists as the dimer of synthesis, or especially It is to be generated when there is free cysteine monomeric peptide and dimerization under oxidative conditions.In some embodiments, dimerization Body is homodimer.In other embodiments, dimer is heterodimer.

In certain embodiments, peptide dimer inhibitor of the invention is the peptide of two inhibitor peptides comprising the present invention Dimer comprising but be not limited to comprising this paper, for example, in table 3A-3H, table 4A, table 4B, table 5A-5C, table 6, table 7, table 8, table 9, the homodimer or heterodimer of any peptide sequence shown in table 10, table 11, table 12, table 13, table 14 or table 15.

In table 3A-3H, table 4A, table 4B, table 5A-5C, table 6, table 7, table 8, table 9, table 10, table 11, table 12, table 13, table 14 Or the certain amino acid sequences listed in table 15 are shown using the single letter code of amino acid.Monomer inhibitor peptides are wherein only shown Sequence；It should be understood, however, that in certain embodiments, introduction according to the present invention and as example table 3A-3H, table 4A, It is generally shown in table 4B, table 5A-5C, table 6, table 7, table 8, table 9, table 10, table 11, table 12, table 13, table 14 or table 15, makes these Monomer inhibitor peptides (that is, monomelic subunit) dimerization is to form peptide dimer inhibitor.

In certain embodiments, monomelic subunit of the invention can be by suitable coupling part (for example, two and half Guangs Disulphide bridges between propylhomoserin (cysteine in each peptide monomer subunit)), or by another suitable junction portion (including But it is not limited to those of defined herein) dimerization.Some monomelic subunits are shown with the ends C- and the ends N- for including unhindered amina. Therefore, in order to generate peptide dimer inhibitor, monomelic subunit can be modified to eliminate the unhindered amina at the ends C- or the ends N-, by This allows the dimerization on remaining unhindered amina.In addition, in some instances, the ends of one or more monomelic subunits is with being selected from Acylated organic compound below is acylated：Change containing three fluorine amyl groups, acetyl group, octonyl, butyl, amyl, hexyl, palmityl Close object；Trifluoromethyl butyric acid, cyclopentane-carboxylic acid, Cyclopropylacetic acid, 4- fluobenzoic acids, 4- Fluorophenylacetic acids, 3- phenylpropionic acids, four - 4 carboxylic acid of hydrogen -2H- pyrans, succinic acid and glutaric acid.In some instances, monomelic subunit includes free carboxy end and free amine group It holds, thus user can selectively modify the subunit to realize dimerization in desired end.Therefore, people in the art Member understands that monomelic subunit of the invention can be modified selectively to obtain the single specific amine for it is expected dimerization.

It should also be understood that the ends the C- residue of monomelic subunit disclosed herein is optionally amide.In addition, it should be understood that certain In embodiment, promote the dimerization at the ends C- by using the suitable amino acid side chain with amine functional group, as this field is logical Often understood.About the ends N- residue, it is commonly understood that dimerization can be realized by the unhindered amina of terminal residue, Huo Zheke To be realized by using the suitable amino acid side chain with unhindered amina, as commonly understood in the art.

The junction portion of connection monomelic subunit may include any structure compatible with teaching herein, length and/or big It is small.In at least one embodiment, junction portion is selected from non-limiting group be made up of：Cysteine, lysine, DIG, PEG4, PEG4- biotin, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, ADA, Boc- IDA, glutaric acid, isophthalic acid, 1,3- phenylenediacetic Acids, Isosorbide-5-Nitrae-phenylenediacetic Acid, 1,2- phenylenediacetic Acids, triazine, Boc- triazines, IDA- Biotin, PEG4- biotins, AADA, suitable aliphatic compound, aromatic compound, heteroaromatic compound and point The connector based on polyethylene glycol that son amount is about 400Da to about 40,000Da.The non-limiting reality of suitable junction portion Example is provided in table 2A.

The illustrative junction portions table 2A.

In some embodiments, peptide dimer inhibitor is via junction portion dimerization.In some embodiments, peptide Dimer inhibitor is intermolecular via being formed between two cysteine residues (cysteine in each monomelic subunit) Disulfide bond dimerization.In some embodiments, peptide dimer inhibitor via junction portion and two cysteine residues it Between the intermolecular disulfide bond dimerization that is formed.In some embodiments, intramolecular bond be thioether bond, lactam bond, triazole key, Selenide key, diselenide key or alkene key, rather than disulfide bond.

The example illustration of an embodiment of dimer is shown below：

Compound D.

It will be appreciated by those skilled in the art that connector (for example, the ends C- and N- end connectors) disclosed herein is partly suitable non- Limitative examples, and the present invention may include any suitable junction portion.Therefore, some embodiments of the invention include The homodimer or heterodimer inhibitor peptides be made of two monomelic subunits, the monomelic subunit is selected to be shown in appoints herein Peptide in what table comprising the sequence being presented in any table herein or is made from it, wherein the ends C- of each monomelic subunit or N- (or internal amino acid residue) is held to be connected by any suitable junction portion to provide the dimerization with IL-23R inhibitory activity Body inhibitor peptides.In certain embodiments, connector and the ends N- of monomelic subunit or the ends C- and composition dimer is other The internal amino acid residue of monomelic subunit combines.In certain embodiments, the internal amino acid of connector and a monomelic subunit The internal amino acid residue of other monomelic subunits of residue and composition dimer combines.In other embodiments, connector and two The ends N- of a subunit or the ends C- combine.

In a particular embodiment, inhibitor peptides of the invention include two of monomer inhibitor peptides described herein or More polypeptide sequences.

In one embodiment, peptide dimer inhibitor of the invention includes to be connected via one or more junction portions Two peptide monomer subunits, wherein each peptide monomer subunit includes following or be made up of：7 to 35 amino acid residues, 8 to 35 amino acid residues, 9 to 35 amino acid residues, 10 to 35 amino acid residues, 7 to 25 amino acid residues, 8 to 25 Amino acid residue, 9 to 25 amino acid residues, 10 to 25 amino acid residues, 7 to 20 amino acid residues, 8 to 20 amino Sour residue, 9 to 20 amino acid residues, 7 to 18 amino acid residues, 8 to 18 amino acid residues, 9 to 18 amino acid are residual Base or 10 to 18 amino acid residues, and include the sequence of Formulas I a as described herein.

In a particular embodiment, one or both of monomelic subunit includes Formula X as described herein, Formulas I, Formula II, formula The sequence of any one in III, formula IV or Formula V.

In certain embodiments, peptide dimer inhibitor includes two peptides connected via one or more junction portions Monomelic subunit, wherein the length of each peptide monomer subunit is 8-20 amino acid and includes any one in formula as described herein Sequence, such as Formula X, Formulas I, Formula II, formula III, formula IV or Formula V.In certain embodiments, peptide dimer inhibitor include via Two peptide monomer subunits of one or more junction portion connections, wherein the length of each peptide monomer subunit is 8-20 amino Acid, and include the sequence of any one in Formula X, Formulas I, Formula II, formula III, formula IV or Formula V.

In certain embodiments, peptide dimer inhibitor or its pharmaceutically acceptable salt or solvate have Formula IV Structure：

(R¹-X-R²)₂-L(VI)

Wherein each R¹It is independently not present, is that key (for example, covalent bond) or R1 are selected from hydrogen, C1-C6 alkyl, C6-C12 virtues Base, C6-C12 aryl C1-C6 alkyl, C1-C20 hydrocarbon acyl groups, and include the individual PEGylated forms of aforementioned any one Or the PEGylated forms as introns；

Each R²It is independently not present, for key (for example, covalent bond) or is selected from OH or NH₂；

L is junction portion；And

Each X is the peptide monomer subunit of independent choice, and it includes length for amino acid residue below or to be made from it：7 To 35 amino acid residues, 8 to 35 amino acid residues, 9 to 35 amino acid residues, 10 to 35 amino acid residues, 7 to 25 A amino acid residue, 8 to 25 amino acid residues, 9 to 25 amino acid residues, 10 to 25 amino acid residues, 7 to 20 ammonia Base acid residue, 8 to 20 amino acid residues, 9 to 20 amino acid residues, 7 to 18 amino acid residues, 8 to 18 amino acid Residue, 9 to 18 amino acid residues or 10 to 18 amino acid residues, respectively contain Formulas I a described herein sequence or It is made from it.In a particular embodiment, each peptide monomer subunit includes following or is made up of：Formula as described herein Ix, Formulas I a, Formulas I b, Formulas I c, Formulas I d, Formulas I e, Formulas I f, Formulas I g, Formulas I h, Formulas I i, Formulas I j, Formulas I k, Formulas I l, Formulas I m, Formulas I n, formula Io, Formulas I p, Formulas I q, Formulas I q ', Formulas I s, Formulas I t, Formula II a, Formula II b, Formula II c, Formula II d, formula III a, formula III b, formula III c, formula The sequence of IIId, formula III e, formula IV a, formula IV b or Formula V a-Vh.

In certain embodiments, one or two peptide monomer subunit of peptide dimer inhibitor for example via X4 and X9 it Between intramolecular bond cyclisation.In the certain embodiments for being wherein cyclized two peptide monomer subunits, in two peptide monomer subunits Between intramolecular bond can be same or different.In certain embodiments, one or two intramolecular bond is two sulphur Key, thioether bond, lactam bond, selenide key, two selenium keys or alkene key.

In one embodiment, one or two cyclisation peptide monomer subunit in X4 and X9 independently selected from Cys, Pen, hCys, D-Pen, D-Cys and D-hCys, and intramolecular bond is disulfide bond.

In one embodiment, one or two cyclisation peptide monomer subunit in X4 and X9 independently selected from Glu, Asp, Lys, Orn, Dap, Dab, D-Dap, D-Dab, D-Asp, D-Glu and D-Lys, and intramolecular bond is lactam bond.

In one embodiment, the X4 in the peptide monomer subunit of one or two cyclisation and X9 are each independently selected from β- Azido-Ala-OH, propargylglycine, and peptide dimer inhibitor is cyclized by triazole ring.In one embodiment, X4 and X9 in the peptide monomer subunit of one or two cyclisation are each independently selected from 2- allylglycines, 2- (3 '-butylene Base) glycine, 2- (4 '-pentenyl) glycine, 2- (5 '-hexenyl) glycine, and peptide dimer inhibitor is via cyclization Metathesis reaction is cyclized to generate corresponding alkene/' stapler peptide '.

In one embodiment, the X4 of the peptide monomer subunit of one or two cyclisation is 2- chloromethyl benzoic acids, sulfydryl The chloro- acetic acid of propionic acid, mercaptobutyric acid, 2-, the chloro- propionic acid of 3-, the chloro- butyric acid of 4-, the chloro- isobutyric acids of 3- or hSer (Cl), one or two The X9 of the peptide monomer subunit of cyclisation is hSer (Cl), Cys, Pen, hCys, D-Pen, D-Cys or D-hCys, and intramolecular bond For thioether bond.

In one embodiment, the X4 of the peptide monomer subunit of one or two cyclisation is that 2- chloromethyl benzoic acids, 2- are chloro- The chloro- propionic acid of acetic acid, 3-, the chloro- butyric acid of 4-, the chloro- isobutyric acids of 3-, hSer (Cl) or Sec, the peptide monomer subunit of one or two cyclisation X9 be hSer (Cl) or Sec, and intramolecular bond be selenide key.

In certain embodiments, one or two intramolecular bond is two selenium keys.

In certain embodiments, one or two peptide monomer subunit is linear or is not cyclisation.

In the specific embodiment of peptide dimer inhibitor, each X7 and each X11 are W.In certain embodiments In, each X7 and each X11 are W, and each X10 is Y, and each X4 and X9 are C.In certain embodiments, each X7 and each X11 is W, and each X10 is Y, and each X4 and X9 is the amino acid that can form intramolecular bond, the molecule Internal key is thioether bond, lactam bond, triazole key, selenide key, two selenium keys or alkene key.

In certain embodiments of peptide dimer inhibitor, one or two peptide monomer subunit has herein for example in table Structure shown in 3A-3I, or comprising amino acid sequence shown in this article, for example, as shown in table 3A-3I, or The wherein described peptide dimer inhibitor of person has such as structure shown in table 3F herein, or includes amino shown in this article Acid sequence, for example, as shown in table 3F.

In a particular embodiment, each R¹Independently be key (for example, covalent bond) or selected from hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, C1-C20 hydrocarbon acyl groups, and include the individual poly- second two of aforementioned any one Alcoholization form or PEGylated forms as introns.In a particular embodiment, the N-terminal of each subunit includes being selected from Hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, C1-C20 hydrocarbon acyl group and include any one of aforementioned The part of individual PEGylated forms or the PEGylated forms as introns of aforementioned any one.

With it is shown in this article it is various in any inhibitor peptides of any one certain embodiments in, each R¹(or N End part) be selected from methyl, acetyl group, formoxyl, benzoyl, trifluoroacetyl group, isovaleryl, isobutyryl, octyl, and The conjugated amide of lauric acid/dodecanoic acid, hexadecylic acid and γ-Glu- hexadecylic acids.

In a particular embodiment, each R²(or C-terminal part) independently be key (for example, covalent bond) or selected from OH or NH₂。

With it is shown in this article it is various in any inhibitor peptides of any one specific embodiment in, each X includes Below or it is made up of：7 to 35 amino acid residues, 8 to 35 amino acid residues, 9 to 35 amino acid residues, 10 to 35 A amino acid residue, 7 to 25 amino acid residues, 8 to 25 amino acid residues, 9 to 25 amino acid residues, 10 to 25 ammonia Base acid residue, 7 to 18 amino acid residues, 8 to 18 amino acid residues, 9 to 18 amino acid residues or 10 to 18 amino Sour residue.

In a particular embodiment, one or two X includes following or is made up of：Appoint in formula as described herein The sequence of one.In certain embodiments of any inhibitor peptides (including dimer) shown in this article or formula, X does not include U.S. Amino acid sequence shown in state's patent application publication the US2013/0029907th is not made from it.At shown in this article In certain embodiments of what inhibitor peptides (including dimer) or formula, X does not include U.S. Patent Application Publication No. US2013/ Amino acid sequence shown in No. 0172272 is not made from it.

In the specific implementation of the inhibitor peptides (monomer and dimer) of the present invention of the Cys comprising Cys and X9 of X4 In scheme, X4 Cys and X9 Cys are connected by disulphide bridges.

In the specific embodiment of the inhibitor peptides of the present invention, each X7 and each X11 are not all W.

In the specific embodiment of the inhibitor peptides of the present invention, each X7 and each X11 are W.

In the specific embodiment of the inhibitor peptides of the present invention, each X7 and each X11 are W, X10 Y and X4 It is C with X9.

In certain embodiments, at least two cysteines in peptide dimer inhibitor by intramolecular or molecule Between disulphide bridges connection.

Either one or two monomelic subunit in being present in peptide dimer inhibitor is (for example, Ix, Ia-It, in the feelings of permission Under condition) specific embodiment in, X4 and X9 are Cys.

Either one or two monomelic subunit in being present in peptide dimer inhibitor is (for example, Ix, Ia-It, in the feelings of permission Under condition) specific embodiment in, X7 and X11 are W.

Either one or two monomelic subunit in being present in peptide dimer inhibitor is (for example, Ia-It, the case where allowing Under) specific embodiment in, X7 and X11 are W, and X10 Y and X4 and X9 are Cys.

Either one or two monomelic subunit in being present in peptide dimer inhibitor is (for example, Ia-It, the case where allowing Under) specific embodiment in, X15 be Gly or Ser.

Either one or two monomelic subunit in being present in peptide dimer inhibitor is (for example, Ia-It, the case where allowing Under) specific embodiment in, X16 be AEA or AEP.

Either one or two monomelic subunit in being present in peptide dimer inhibitor is (for example, Ia-It, the case where allowing Under) specific embodiment in, X10 be Tyr or Phe or Tyr or Phe analog.

Either one or two monomelic subunit in being present in peptide dimer inhibitor is (for example, Ia-It, the case where allowing Under) specific embodiment in, X11 Trp.

In the specific embodiment of any peptide dimer inhibitor described herein, either one or two R¹For hydrogen.

The present invention peptide dimer inhibitor specific embodiment in, junction portion (L) be it is described herein or Person's any connector shown in table 2A or 2B.In certain embodiments, L is lysine connector, diethylene glycol connector, imido Base oxalic acid (IDA) connector, β-Ala- iminodiacetic acids (β-Ala-IDA) connector or PEG connectors.

In the different embodiments of any peptide dimer inhibitor, peptide monomer subunit respectively via its end N-, the ends C- or Internal amino acid residue is connect with junction portion.

In certain embodiments of any peptide dimer inhibitor, the ends N- of each peptide monomer subunit pass through junction portion Connection.

In certain embodiments of any peptide dimer inhibitor, the ends C- of each peptide monomer subunit pass through junction portion Connection.

In certain embodiments of any peptide dimer inhibitor, each peptide monomer subunit is by being connected to internal amino The junction portion connection of acid.

In certain embodiments of peptide dimer inhibitor, junction portion is diethylene glycol connector, iminodiacetic acid (IDA) connector, β-Ala- iminodiacetic acids (β-Ala-IDA) connector or PEG connectors.

In certain embodiments of peptide dimer inhibitor, one or two peptide monomer subunit has in embodiment Structure shown in any of table, or the amino acid sequence that is shown comprising any of table in embodiment.

In certain embodiments of any inhibitor peptides (including dimer) shown in this article or formula, X does not include the U.S. Amino acid sequence shown in patent application publication the US2013/0029907th is not made from it.Shown in this article any In certain embodiments of inhibitor peptides (including dimer) or formula, X does not include U.S. Patent Application Publication No. US2013/ Amino acid sequence shown in No. 0172272 is not made from it.

In the specific embodiment of the inhibitor peptides of the present invention, each X7 and each X11 are W, X10 Y and X4 It is Pen with X9.

In certain embodiments, at least two cysteine residues in peptide dimer inhibitor by intramolecular or divide Disulphide bridges connection between son.

Inhibitor peptides conjugate and biopolymer

In certain embodiments, inhibitor peptides of the invention (including monomer and dimer) include one or more conjugated Chemical substituents be referred to alternatively as half-life extension moiety herein such as lipophilic substituent and polymer moieties.It does not wish It hopes bound by any particular theory, it is believed that, lipophilic substituent and the albumin combination in blood flow, to protect inhibitor peptides It degrades from enzyme, and therefore increases its half-life period.Additionally it is believed that polymer moieties increase half-life period and reduce in blood flow Clearance rate.

In a further embodiment, arbitrary inhibitor peptides, for example, formula (Va)-(Vh) peptide, also include in inhibitor The junction portion of existing amino acid residue connection, for example, junction portion can with the side chain of the arbitrary amino acid of inhibitor peptides, The N-terminal amino acid of inhibitor peptides or the C-terminal amino acid of inhibitor peptides combine.

In a further embodiment, arbitrary inhibitor peptides, for example, formula (Va)-(Vh) peptide, also include in inhibitor The half-life extension moiety of existing amino acid residue connection, such as half-life extension moiety can be with the arbitrary ammonia of inhibitor peptides The C-terminal amino acid of the side chain of base acid, the N-terminal amino acid of inhibitor peptides or inhibitor peptides combines.

In a further embodiment, arbitrary inhibitor peptides, for example, formula (Va)-(Vh) peptide, also include be connected to and press down The half-life extension moiety for the junction portion that amino acid residue present in preparation connects, such as half-life extension moiety can connect It is connected to and is combined with the C-terminal amino acid of the side chain of the arbitrary amino acid of inhibitor peptides, the N-terminal amino acid of inhibitor peptides or inhibitor peptides Junction portion.

In a particular embodiment, IL23R analogs include the half-life extension moiety with structure as follows, wherein N=0 to 24 or n=14 to 24：

In certain embodiments, IL23R analogs of the invention include half-life extension moiety shown in table 7.

7. illustrative half-life extension moiety of table

In certain embodiments, half-life extension moiety is directly combined with inhibitor peptides, and in other embodiments, Half-life extension moiety is via junction portion, such as any of the junction portion described in table 6 or table 8, with inhibitor peptides knot It closes.

8. illustrative junction portion of table

In a particular embodiment, inhibitor peptides of the invention include institute in arbitrary junction portion and table 7 shown in table 8 The arbitrary half-life extension moiety shown, including arbitrary following combination shown in table 9a.

The example combinations of connector and half-life extension moiety in table 9a. inhibitor peptides

In some embodiments, multiple connect may be present between peptide and conjugated part (such as half-life extension moiety) Head, for example, as described in table 9b.

The example combinations of table 9b. inhibitor peptides center tap and half-life extension moiety

The illustrative examples of the inhibitor peptides of the present invention are illustrated below comprising there is conjugate connector and/or partly decline The inhibitor peptides of phase prolongation.Unless otherwise indicated, all amino acid are all L amino acid.The invention also includes the suppressions of these peptides The salt form of any one of preparation, including but not limited to its acetate.

Embodiment 1：Ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- carboxylics Base-oxinane]-ENN-NH₂

Embodiment 1a：Ac- [(D)-Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]- [4- amino -4- carboxyls-oxinane]-ENN-NH₂

Embodiment 2：Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- Carboxyl-oxinane]-[Lys (Ac)]-NN-NH₂

Embodiment 3：Ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)-(connector-half-life extension moiety)]- [2-Nal]-[4- amino -4- carboxyls-oxinane]-ENN-NH₂

Embodiment 3a：[[(connector-partly declines 4- (2- amino ethoxies)-Phe Ac- [(D)-Arg] ring [[Abu]-QTWQC]- Phase prolongation)]-[2-Nal]-[4- amino -4- carboxyls-oxinane]-ENN-NH₂

Embodiment 4：Ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- carboxylics Base-oxinane]-[Lys (connector-half-life extension moiety)]-NN-NH₂

Embodiment 4a：Ac- [(D)-Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]- [4- amino -4- carboxyls-oxinane]-[Lys (connector-half-life extension moiety)]-NN-NH₂

Embodiment 5：Ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- carboxylics Base-oxinane]-ENN- [Lys (connector-half-life extension moiety)]-NH₂

Embodiment 5a：Ac [(D)-Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]- [4- amino -4- carboxyls-oxinane]-ENN- [Lys (connector-half-life extension moiety)]-NH₂

Embodiment 6：[half-life extension moiety-connector]-[ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies Base)]-[2-Nal]-[4- amino -4- carboxyls-oxinane]-ENN-NH₂

Embodiment 6a：[half-life extension moiety-connector]-[(D)-Arg]-[ring [[Abu]-QTWQC]-[Phe [4- (2- Amino ethoxy)]-[2-Nal]-[4- amino -4- carboxyls-oxinane]-ENN-NH₂

Embodiment 7：[half-life extension moiety-connector]-[Pen]-NTWQ- [Pen]-[Phe [4- (amino ethoxy)]- [2-Nal]-[4- amino -4- carboxyls-oxinane]-[Lys (Ac)]-NN-NH₂

Embodiment 8：Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (amino ethoxy)]-[2-Nal]-[4- amino -4- carboxylics Base-oxinane]-[Lys (Ac)]-NN- [Lys (connector-half-life extension moiety)]-NH₂

Embodiment 9：Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (amino ethoxy)-(connectors-Increased Plasma Half-life portion Point)]-[2-Nal]-[4- amino -4- carboxyls-oxinane]-[Lys (Ac)]-NN-NH₂

Embodiment 10：Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (amino ethoxy)]-[2-Nal]-[4- amino -4- Carboxyl-oxinane]-[Lys (connector-half-life extension moiety)]-NN-NH₂

In certain embodiments, include the peptide suppression of the present invention of conjugated chemical substituents (i.e. half-life extension moiety) The half-life period of preparation be identical inhibitor peptides (but being free from conjugated chemical substituents) half-life period at least 100%, extremely Few 120%, at least 150%, at least 200%, at least 250%, at least 300%, at least 400% or at least 500%.In certain realities It applies in scheme, lipophilic substituent and/or polymer moieties increase permeability and/or inhibitor peptides that inhibitor peptides penetrate epithelium Delay in lamina propria.In certain embodiments, including the inhibitor peptides of the present invention of conjugated chemical substituents penetrate The permeability of epithelium and/or the delay in lamina propria are the half of identical inhibitor peptides (but being free from conjugated chemical substituents) Decline the phase 100%, at least 120%, at least 150%, at least 200%, at least 250%, at least 300%, at least 400% or at least 500%.

In one embodiment, one or more of inhibitor peptides of the invention amino acid residue is (for example, Lys is residual Base) side chain and lipophilic substituent it is conjugated (for example, covalent linkage).Lipophilic substituent can be with the original in amino acid side chain Sub- covalent bonding, or optionally can be conjugated via one or more introns and amino acid side chain.Introns (work as presence When) interval can be provided between peptide analogues and lipophilic substituent.In a particular embodiment, inhibitor peptides include table 2- Part arbitrarily conjugated shown in table 5.

In certain embodiments, lipophilic substituent can include to have 4 to 30 C atoms, for example, at least 8 or 12 C atoms, and preferably 24 C atoms or less or 20 C atoms or less hydrocarbon chain.Hydrocarbon chain can be linear chain or branched chain , and can be saturated or unsaturated.In certain embodiments, hydrocarbon chain is formed with amino acid side chain or introns connects The part substitution of socket part point, such as acyl group, sulfonyl, N atoms, O atom or S atom.In some embodiments, hydrocarbon chain is by acyl Base replaces, and therefore hydrocarbon chain can form hydrocarbon acyl moiety, such as palmityl, caproyl, lauroyl, myristoyl Or stearyl.

Lipophilic substituent can be with the arbitrary amino acid side chain conjugation in the inhibitor peptides of the present invention.In certain embodiment party In case, amino acid side chain includes carboxyl, hydroxyl, mercaptan, amide or amine groups, for being formed with introns or lipophilic substituent Ester, sulfonyl ester, thioesters, amide or sulfonamide.For example, lipophilic substituent can with Asn, Asp, Glu, Gln, His, Lys, Arg, Ser, Thr, Tyr, Trp, Cys or Dbu, Dpr or Orn are conjugated.In certain embodiments, lipophilic substituent and Lys It is conjugated.The amino acid of Lys is shown as in any formula provided herein (to be added to lipophilic by such as Dbu, Dpr or Orn Property substituent group in the case of) substitution.

In certain embodiments, can by by one or more amino acid side chains in chemical part and peptide it is conjugated come The inhibitor peptides of the present invention are modified, for example, to enhance stability, increase permeability or enhancing drug-like properties.For example, N (ε), β-carboxyl of aspartic acid or the γ-carboxyl of glutamic acid of lysine N (ε) can be appropriate functionalized.Therefore, it is The peptide for generating modification, can suitably modify the amino acid in peptide.In addition, in some instances, side chain is with being selected from Acylated organic compound below is acylated：Three fluorine amyl groups, acetyl group, Octonyl, butyl, amyl, hexyl, palmityl, fluoroform Base butyric acid, cyclopentane-carboxylic acid, Cyclopropylacetic acid, 4- fluobenzoic acids, 4- Fluorophenylacetic acids, 3- phenylpropionic acids, tetrahydrochysene -2H- pyrans -4 Carboxylic acid, succinic acid, glutaric acid or bile acid.It will be appreciated by those skilled in the art that a series of conjugate can be connected, for example, PEG4, different glu and combinations thereof.It will be appreciated by those skilled in the art that the amino acid in peptide can by equal row (isosterically) Substitution, for example, Lys can be substituted by Dap, Dab, α-MeLys or Orn.The example of the residue of modification in peptide is shown in table 1B In.

The lysine of modification in table 1B. peptides, the example of Asp and Asn

In other embodiments of the present invention, alternatively, or in addition, the present invention inhibitor peptides in one or more The side chain of a amino acid residue is conjugated with polymer moieties, for example, to increase dissolubility and/or in vivo (such as in blood plasma In) half-life period and/or bioavilability.It is also known that such modification reduces the clearance rate of human cytokines and peptide, (such as kidney is clear Except rate).

" polyethylene glycol " or " PEG " used herein are the polyether compounds of general formula H- (O-CH2-CH2) n-OH.PEG Be referred to as polyethylene oxide (PEO) or polyoxyethylene (POE), this depend on their molecular weight, PEO, PEE used herein or The oligomer or polymer of POG finger ring oxidative ethanes.These three names are synonymous in chemistry, but PEG tends to refer to molecule Quality is less than the oligomer and polymer of 20,000Da, and PEO tends to refer to the polymer that molecular mass is more than 20,000Da, and POE tends to refer to the polymer of any molecular mass.PEG and PEO is liquid or the solid of low melting point, this depends on their point Son amount.In entire disclosure, this 3 names indistinguishably use.PEG is prepared by the polymerization of ethylene oxide and commercially available is obtained Obtain the molecular weight of the wide scope of 300Da to 10,000,000Da.Although the PEG and PEO of different molecular weight are used for different applications In, and since chain length effect has different physical characteristics (such as viscosity), but their chemical characteristic is almost the same. Polymer moieties are preferably water-soluble (amphiphilic or hydrophilic), nontoxic and pharmaceutical inert.Suitable polymer Part includes polyethylene glycol (PEG), the homopolymer of PEG or copolymer, the monomethyl substituted polymer (mPEG) of PEG or polyoxy second Alkene glycerine (POG).See, e.g., Int.J.Hematology 68：1(1998)；Bioconjugate Chem.6：150 (1995)；With Crit.Rev.Therap.Drug Carrier Sys.9：249(1992).It is also contemplated by for extension half-life period PEG prepared by purpose, for example, the alkoxy end-capped polyalkylene oxide (POA ' s) of single activation, the poly- second two blocked such as mono methoxy Alcohol (mPEG ' s)；Also include the polyethylene oxide (ethylene glycol) or other PEG derivatives that bidifly is lived.The weight of suitable polymer Difference is very big, generally selects the weight of about 200Da to about 40,000Da or about 200Da to about 60,000Da for purposes of the present invention Amount.In certain embodiments, the PEG for the use of molecular weight being 200 to 2,000 or 200 to 500.Different form can also be used PEG, it is simple function methyl ether PEG or the poly- (second two of methoxyl group that this, which depends on the common initiator of the initiator-that uses of polymerization process, Alcohol) (being abbreviated as mPEG).

The PEG of low molecular weight can also be obtained in the form of being referred to as monodispersed, uniform or discrete pure oligomer. These are in certain embodiments of the present invention.

Also it can get the PEG with different solids：There are three distribute ramiform PEG tools to ten from center core group PEG chains；Starlike PEG has 10 to the 100 PEG chains distributed from center core group；And pectination PEG has multiple lead to The PEG chains being often grafted on polymer backbone.PEG can also be linear.The digital representation for usually including in the title of PEG (such as the PEG of n=9 is by the average molecular weight with about 400 dalton, and will be marked as their average molecular weight PEG 400)。

" Pegylation " used herein is the behavior of PEG structures and the inhibitor peptides covalent coupling of the present invention, then It is referred to as " inhibitor peptides of Pegylation ".In certain embodiments, the PEG of Pegylation side chain be molecular weight about The PEG of 200 to about 40,000.In some embodiments, Formulas I, Formulas I ' or Formulas I " the introns of peptide be Pegylation. In certain embodiments, the PEG of Pegylation introns be PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10 or PEG11.In certain embodiments, the PEG of Pegylation introns is PEG3 or PEG8.

Other suitable polymer moieties include polyaminoacid, as polylysine, poly-aspartate and polyglutamic acid (referring to Such as Gombotz, et al. (1995), Bioconjugate Chem., vol.6：332-351；Hudecz, et al. (1992), Bioconjugate Chem., vol.3,49-57 and Tsukada, et al. (1984), J.Natl.Cancer Inst., Vol.73,：721-729.Polymer moieties can be straight chain or branch.In some embodiments, with 500-40, The molecular weight of 000Da, such as 500-10,000Da, 1000-5000Da, 10,000-20,000Da or 20,000-40,000Da.

In some embodiments, inhibitor peptides of the invention can include two or more such polymer moieties, In this case, the total molecular weight of all such parts will usually be fallen into range provided above.

In some embodiments, polymer moieties are coupled and (pass through covalent linkage) amino, the carboxylic to amino acid side chain On base or mercapto.Certain examples are the ε amino of the mercapto and Lys residues of Cys residues, and can also relate to Asp and Glu The carboxyl of residue.

Technical staff is by the known appropriate technology that can be utilized for coupling reaction.It is, for example, possible to use available commercially from The peg moiety for carrying methoxyl group is coupled to by the reagent of Nektar Therapeutics AL by dimaleoyl imino connection On the mercapto of Cys.About the detailed content of appropriate chemical, referring further to WO 2008/101017 and reference text cited above It offers.Maleimide-functionalised PEG can also be conjugated on the sulfydryl of side chain Cys residues.

As used herein, the oxidation of disulfide bond can occur in a step or be two step process.As used herein, for Single step aoxidizes, and during assembly usually using trityl-protecting group, permission deprotects during cutting, subsequent solution oxygen Change.When needing second disulfide bond, Native Oxide or selective oxidation are selected.For needing the selective oxygen of orthogonal protecting group For change, Acm and trityl are used as the protecting group of cysteine.Cutting leads to the shifting of a protection pair of cysteine Remove, allow this to oxidation.Then second oxidation deprotection step of the cysteine by Acm radical protections is carried out.For Trityl-protecting group is used for all cysteines, allows the natural folding of peptide by Native Oxide.Technical staff uses known To carry out the appropriate technology of oxidation step.

Make several chemical parts (including poly- (ethylene) glycol) and official present in 20 kinds of naturally occurring amino acid Can group's reaction, the functional group such as, for example, existing in ε amino, cysteine amino in lysine amino acid residue Mercaptan or other nucleophilic amino acid side chains.When making multiple naturally occurring amino acid be reacted in inhibitor peptides, these are non- The chemical reaction of specificity generates final inhibitor peptides, and the final inhibitor peptides are containing there are many different from inhibitor peptides The peptide isomers that poly- (ethylene) glycol chains of one or more on position are conjugated.

One advantage of certain embodiments of the present invention includes can be one or more with unique function by mixing The non-natural amino acid of group adds one or more chemical parts (such as PEG), the unique functional group by chemical mode with The PEG of activation reacts, and the PEG of the activation is not reacted with natural amino acid present in inhibitor peptides.For example, azido compound Group and alkyne groups are not reacted with all naturally occurring functional groups in albumen.Therefore, can it is expected in inhibitor peptides One or more specific sites of PEG or another trims mix non-natural amino acid, and without undesirable non-specificity Reaction.In certain embodiments, the specific chemistry involved in reaction causes the stabilization between PEG chains and inhibitor peptides covalently to connect It connects.Furthermore, it is possible to carry out such reaction under the mild aqueous conditions for not destroying most of peptides.In certain embodiments, non- Native amino acid residues are AHA.

It is connected to the chemical part on natural amino acid in number and range limit system.In contrast, it is connected to non- The useful chemical substance of significantly larger range may be used in chemical part on natural amino acid, thus by chemical part and target point Son connection.Substantially, any target molecule (includes comprising non-natural amino acid (for example, the reaction that can be connected containing chemical part The non-natural amino acid of site or side chain, such as aldehyde-or the derivative amino acid of ketone -) any albumen (or part thereof)) can conduct Connect the substrate of chemical part.

Many chemical parts can be combined or be connected with specific molecule by a variety of known methods of this field.It is a variety of this Class method is described in U.S. Patent No. 8,568,706.As illustrative examples, azide part is conjugated such as PEG's May be useful in chemical part or other chemical parts described herein.Azide part is as reactive functional Group, and be not present in most of naturally occurring compounds (therefore itself and the native amino in naturally occurring compound Acid is reactionless).Azide also with a limited number of reaction partner carry out selectivity connect and azide it is smaller and It can be introduced into biological sample, without significantly changing molecular size.Allow to mix or be introduced to the one of molecule by azide Kind reaction is Huisgen [3+2] cycloaddition for the azide that copper mediates.The reaction can be used for the poly- second of selectivity of inhibitor peptides Diolation (Tornoe et al., J.Org.Chem.67：3057,2002；Rostovtsev et al., Angew.Chem., Int.Ed.41：596,2002；With Wang et al., J.Am.Chem.Soc.125：3192,2003；Speers et al., J.Am.Chem.Soc., 2003,125,4686).

Illustrative inhibitor peptides and peptide dimer inhibitor, and prepare the side of inhibitor peptides and peptide dimer inhibitor Method

Therefore the present invention provides a variety of inhibitor peptides for being combined or being associated with IL-23, to destroy or block IL-23 and IL- Combination between 23R.

In table 3A-3H, table 4A, table 4B, table 5A-5C, table 6, table 7, table 8, table 9, table 10, table 11, table 12, table 13, table 14 Or exemplary peptides inhibitor of the invention and peptide dimer inhibitor shown in table 15 provide selected monomer inhibitor peptides and The amino acid sequence of peptide dimer inhibitor, and point out junction portion present in peptide dimer inhibitor.According to this paper institutes The scheme of discussion synthesizes and is cyclized a large amount of inhibitor peptides and peptide dimer inhibitor shown in subordinate list.Table E3A-E3H, E4A, E4B, E5A-E5C, E6, E7, E8, E9, E10, E11, E12, E13, E14 or E15 provide selected monomer inhibitor peptides and peptide two Aggressiveness inhibitor inhibits IL-23 that the IC50 values of IL-23 signal transductions are combined or inhibited with IL-23R, such as by measuring phosphorylation- The variation of STAT3 levels is measured, as described in appended embodiment.Show the present invention's in formula (V) and table 2- tables 5 Exemplary peptides inhibitor provides the amino acid sequence of selected inhibitor peptides.These inhibitor peptides are acetates.

The inhibitor peptides of many technology synthesis present invention well known by persons skilled in the art can be passed through.In certain embodiment party In case, technology synthesis, purifying and the dimerising monomeric subunit described in appended embodiment are used.In certain embodiments, The present invention provides the method for generating the inhibitor peptides (or monomer subunit) of the present invention comprising chemical synthesis includes to have herein The peptide of the peptide of described amino acid sequence, the peptide being made from it or consisting essentially of peptide, the amino acid sequence packet Include but be not limited to any amino shown in any one in Formulas I, Formula II, formula III, formula IV, Formula V or Formula IV or table as described herein Acid sequence.In other embodiments, the peptide is re-combined into, without being chemical synthesis.In certain embodiments, Inhibitor peptides are dimer, and the method includes synthesizing two monomelic subunits of peptide dimer inhibitor, then make two Monomelic subunit dimerization is to generate peptide dimer inhibitor.In different implementation scenarios, dimerization is via described herein Any one of a variety of methods are realized.In a particular embodiment, the method for generating inhibitor peptides (or monomer subunit) is also wrapped Including is cyclized inhibitor peptides (or monomer subunit) after its synthesis.In a particular embodiment, cyclisation is via described herein Any one of a variety of methods realize.In certain embodiments, the present invention provide generate the present invention inhibitor peptides (or its Monomelic subunit) method comprising intramolecular bond is introduced between two amino acid residues in peptide, for example, disulfide bond, amide Key or thioether bond, the peptide include peptide with amino acid sequence described herein, are made from it or consisting essentially of, The amino acid sequence include but not limited to Formulas I, Formula II, formula III, formula IV, Formula V or Formula IV or appended embodiment, table or Any amino acid sequence shown in any one in sequence table.

In relevant embodiment, the present invention include encode polypeptide polynucleotides, the polypeptide have Formulas I, Formula II, Sequence shown in any one in formula III, formula IV, Formula V or Formula IV or appended embodiment, table or sequence table.

In addition, the present invention includes carrier, for example, expression vector, it includes the polynucleotides of the present invention.

Therapy

In certain embodiments, the present invention includes the method for inhibiting IL-23 to be combined with the IL-23R on cell comprising IL-23 and the inhibitor peptides of the present invention is set to contact.In certain embodiments, cell is mammalian cell.It is being embodied In scheme, the method carries out in vitro or in vivo.Can by various routine experiment methods known in the art and analysis come Measure the inhibition combined.

In certain embodiments, the present invention includes inhibiting the method for the IL-23 signal transductions in cell comprising is made IL-23 is contacted with the inhibitor peptides of the present invention.In certain embodiments, cell is mammalian cell.In specific embodiment party In case, the method carries out in vitro or in vivo.It in a particular embodiment, can be by measuring the phosphorylation-in cell STAT3 is horizontal to be changed to measure the inhibition of IL-23 signal transductions.

In some embodiments, the present invention is provided to treat to suffer from IL-21 or IL-23R (for example, IL-23/IL- The activation of 23R signal transduction pathways) the relevant patient's condition or indication object method, wherein the method includes to described right As the inhibitor peptides of the application present invention.In one embodiment, treatment is provided with unsuitable, imbalance or increased The method of the object for the patient's condition or indication that IL-23 or IL-23R activity or signal transduction are characterized comprising applied to individual It is enough the inhibitor peptides of the present invention for the amount for inhibiting the IL-23 in object to be combined with IL-23R (partially or completely).Specific In embodiment, the inhibition that IL-23 is combined with IL-23R is happened in certain organs or the tissue of object, for example, stomach, small intestine, Big intestines colon, intestinal mucosa, lamina propria, peyer's patches, lymphonodi mesenterici or lymphatic ducts.

In some embodiments, the method for the present invention includes the inhibitor peptides that the present invention is provided to object in need. In a particular embodiment, object in need has been diagnosed with the relevant diseases of IL-23/IL-23R or illness or It is determined under the risk in development and the relevant diseases of IL-23/IL-23R or illness.In a particular embodiment, described right As for mammal.

In certain embodiments, disease or illness are autoimmune inflammation and relevant disease and illness, such as multiple Hardening, asthma, rheumatoid arthritis, inflammatory bowel disease (IBD), juvenile form IBD, young type IBD, Crohn disease, sarcoidosis, Systemic loupus erythematosus, ankylosing spondylitis (axis joint of vertebral column is scorching), psoriasis arthropathica or psoriasis.It is being embodied In scheme, disease or illness are psoriasis (for example, psoriasis in plaques, psoriasis punctata, reversed property psoriasis, pustule type Psoriasis, palmoplantar pustulosis, psoriasis vulgaris or erythrodermic psoriasis), peculiar smell dermatitis, acne ectopica, ulcer Property colitis, Crohn disease, chylous diarrhea (nontropical sprue), with the relevant enteropathy of seronegative arthropathy, Microscopic colitis, collagenous colitis, eosinophilic gastroenteritis/esophagitis, with radiotherapy or the relevant colitis of chemotherapy, With the relevant colitis of congenital immunity illness, chronic granulo matosis, glycogen storage disease 1b of such as 1 type of leukocyte adhesion deficiency disease Type, Hermansky-Pudlak syndromes, Chediak-Higashi syndromes, Wiskott-Aldrich syndromes, nodus hemorrhoidalis Caused haustrum inflammation, human primary gastrointestinal cancers, pancreatitis, insulin-dependent diabetes mellitus, breast after enterectomy and ileoanal anastomosis It is adenositis, cholecystitis, cholangitis, primary biliary cirrhosis, the relevant enteropathy of virus, pericholangitis, chronic bronchitis, slow Property sinusitis, asthma, uveitis or graft versus host disease(GVH disease).

In certain relevant embodiments, the present invention provide selectively inhibit IL-23 in object in need or The method of IL-23R signal transductions (or combination of IL-23 and IL-23R) comprising the peptide suppression of the present invention is provided to the object Preparation.In a particular embodiment, the present invention includes the IL-23 or IL- in the roads GI for selectively inhibit object in need The method of 23R signal transductions (or combination of IL-23 and IL-23R) comprising provide this hair by being administered orally to the object Bright inhibitor peptides.In a particular embodiment, exposure of the inhibitor peptides of application in GI organizes (for example, small intestine or colon) Than greatly at least 10 times, at least 20 times, at least 50 times or at least 100 times of exposure in blood.In a particular embodiment, this hair Bright includes IL23 or IL23R signal transductions (or the knot of IL23 and IL23R selectively inhibited in the roads GI of object in need Close) method comprising provide inhibitor peptides to the object, wherein inhibitor peptides do not block the phase between IL-6 and IL-6R Interaction or not antagonism IL-12 signal transduction pathways.In other relevant embodiment, the present invention includes inhibiting GI inflammation And/or neutrophil cell infiltrates the method to GI comprising the inhibitor peptides of the present invention are provided to object in need.One In a little embodiments, the method for the present invention includes the inhibitor peptides of the present invention are provided to object in need (that is, the first treatment Agent) with the combination of second therapeutic agent.In certain embodiments, to object apply inhibitor peptides before and/or at the same time of and/or it Afterwards, second therapeutic agent is provided to the object.In a particular embodiment, second therapeutic agent is anti-inflammatory agent.In certain embodiment party In case, second therapeutic agent is non-steroidal anti-inflammatory drugs, steroids or immunomodulator.In another embodiment, the method packet It includes to object and applies third therapeutic agent.In certain embodiments, second therapeutic agent is the antibody in conjunction with IL-23 or IL-23R.

In a particular embodiment, inhibitor peptides or the pharmaceutical composition comprising inhibitor peptides are suspended in sustained-release matrix. Sustained-release matrix used herein is by (can usually be gathered by enzymatic hydrolysis or acid and alkali hydrolysis or the material by dissolving degradation Close object) made of matrix.Once in insert, the matrix is worked by enzyme and body fluid.Sustained-release matrix is ideally selected from Biocompatible materials, such as liposome, polylactide (polylactic acid), polyglycolide (polymer of glycolic), polylactide- Co- glycolide (copolymer of lactic acid and glycolic) polyanhydrides, poly- (ortho acid) ester, polypeptide, hyaluronic acid, collagen, chondroitin sulfate It is element, carboxylic acid, aliphatic acid, phosphatide, polysaccharide, nucleic acid, polyaminoacid, amino acid (such as phenylalanine, tyrosine, isoleucine), more Nucleotide, polyethylene propylene, polyvinylpyrrolidone and silicone.One embodiment of biodegradable matrix is poly- third friendship The matrix of one of ester, polyglycolide or polylactide-co-glycolide (copolymer of lactic acid and glycolic).

In certain embodiments, the present invention includes including one or more inhibitor peptides and pharmaceutically acceptable of the present invention Carrier, diluent or excipient pharmaceutical composition.Pharmaceutically acceptable carrier, diluent or excipient refer to nontoxic consolidate Body, semisolid or liquid filler, diluent, encapsulating material or any kind of formulation auxiliary agents.It can be by comprising various anti- Bacteriocin and antifungal agent (for example, p-hydroxybenzoate, methaform, phenol sorbic acid etc.) ensure the pre- of microbial action It is anti-.It may also be desired that comprising isotonic agent, such as sugar, sodium chloride.

In certain embodiments, by composition by oral administration, parenteral, in brain pond, in intravaginal, peritonaeum, in rectum, office Portion (such as passing through pulvis, ointment, drops, suppository or transdermal skin patches), pass through sucking (such as intranasal spray), eyes (such as intraocular) Or buccal application.Terms used herein " parenteral " refer to administration mode comprising intravenous, intramuscular, intraperitoneal, breastbone Interior, subcutaneous, intradermal and intra-articular injection and infusion.Therefore, in certain embodiments, compositions formulated is for passing through this Any one of a little administration method are delivered.

In certain embodiments, be used for parenteral injection pharmaceutical composition include pharmaceutically acceptable sterile aqueous or Non-aqueous solution, dispersion, suspension or emulsion and for reconstructing the nothing in sterile injectable solution or dispersion before use Bacterium powder end.Suitable aqueous and non-aqueous carrier, diluent, solvent or medium example include water, ethyl alcohol, polyalcohol (such as Glycerine, propylene glycol, polyethylene glycol etc.), carboxymethyl cellulose and their suitable mixture, beta-cyclodextrin, vegetable oil (such as Olive oil) and injectable organic ester (such as ethyl oleate).Suitable mobility can be maintained by following：Such as by making With coating material (such as lecithin), by maintaining required granular size in the case of a dispersion and by using surface Activating agent.These compositions can also contain adjuvant, such as preservative, wetting agent, emulsifier and dispersant.By being inhaled comprising delay The reagent (such as aluminum monostearate and gelatin) of receipts causes the extension of injectable drug form to absorb.

Injectable depot form includes by forming the micro- of inhibitor peptides in one or more biodegradable polymers Those of made by capsule base, the biodegradable polymer such as polylactide-polyglycolide, poly- (ortho esters), poly- (acid Acid anhydride) and (poly-) glycol (such as PEG).According to the property of the ratio and used specific polymer of peptide and polymer, can control The rate of release of inhibitor peptides processed.Inhibitor peptides also by being embedded in the fat compatible with bodily tissue by reservoir type injectable formulation It is prepared in plastid or microemulsion.

It can sterilize to injectable formulation, for example, being in nothing by being filtered through bacteria retaining filter, or by incorporation The bactericidal agent of bacterium solid composition form carries out, and can be dissolved in or be scattered in nothing by the aseptic solid composite using preceding In bacterium water or other sterile injectable mediums.

Local application includes application to skin or mucous membrane comprising the surface of lung and eyes.Group for local pulmonary application Solution and suspension that object those of (including sucking and intranasal) may be embodied in aqueous and non-aqueous based formulations are closed, and can be made It is standby at dry powder, can be pressurization or normal pressure.In the powder composition of normal pressure, can by form fine crushing activity at Point with comprising for example, the pharmaceutically acceptable inert carrier that diameter dimension is up to the large-size of 100 microns of particle mixes and makes With.Suitable inert carrier includes sugar, such as lactose.

Optionally, composition can be pressurized, and contain compressed gas, such as nitrogen or gas propellant.It is liquefied Propellant medium, in fact whole composition can be so that active constituent will not be dissolved in wherein on any significance degree.Add The composition of pressure can also contain surfactant, such as the nonionic surfactant of liquid or solid, or can be solid Anion surfactant.It is preferable to use the solid anionic surfactants of sodium-salt form.

The other forms of local application are to be applied to eyes.The inhibitor peptides of the present invention can be with pharmaceutically acceptable ophthalmology The form of medium delivers so that inhibitor peptides are kept in contact the sufficient period to allow inhibitor peptides to penetrate into eye with eye surface The pupil region of eyeball and interior zone, such as such as anterior chamber, back room, vitreum, aqueous humor, vitreous humor, cornea, iris/eyelashes, crystalline substance Shape body, choroid/retina and sclera.Pharmaceutically acceptable ophthalmology medium can be, for example, ointment, vegetable oil or encapsulating Material.It is alternatively possible to which the inhibitor peptides of the present invention are directly injected into vitreum and aqueous humor.

Composition for rectum or vaginal application includes suppository, can be by by the inhibitor peptides of the present invention and such as The suitable nonirritant excipient or carrier of cupu oil, polyethylene glycol or suppository wax mix to prepare, and the suppository is in room temperature It is solid down but is liquid under body temperature, and therefore fusing and release of active compounds in rectum or vaginal canal.

The inhibitor peptides of the present invention can also be applied in the form of liposome or other carriers based on lipid.Such as this field Known, liposome generally originates from phosphatide or other lipid matters.The hydrating fluid being dispersed in by single-layer or multi-layer in aqueous medium Crystallization liposome.Can use can form any nontoxic, physiologically acceptable and metabolizable lipid of liposome. Other than the inhibitor peptides of the present invention, stabilizer, preservative, excipient can be contained in this composition of liposomal form Deng.In certain embodiments, lipid includes natural and synthesis phosphatide comprising phosphatidyl choline (lecithin) and phosphatidyl Serine.The method for forming liposome is known in the art.

The aseptic aqueous solution of inhibitor peptides can be included by being ready to use in the pharmaceutical composition suitable for parenteral administration of the present invention And/or suspension, make itself and the blood of recipient etc. usually using sodium chloride, glycerine, glucose, mannitol, D-sorbite etc. It oozes.

In some respects, the present invention is provided to the pharmaceutical compositions of oral delivery.The composition and peptide of the present invention inhibits Agent can be prepared according to any means described herein, technology and/or delivery vehicle for oral administration.In addition, It will be appreciated by those skilled in the art that can carry out modifying or being integrated into the inhibitor peptides of the present invention not public herein It opens, but be well known in the art and oral delivery that peptide is used in compatible system or delivery vehicle.

In certain embodiments, formulations for oral use can include adjuvant (such as resorcinol and/or it is non-from Sub- surfactant such as polyoxyethylene oleyl ether and n-hexadecyl polyvinylether) taking human as the permeability of ground increase intestinal wall, and/ Or enzyme inhibitor (such as pancreatic trypsin inhibitor, diisopropyl fluorophosphate (DFP) (DFF) or Aprotinin) is to inhibit enzyme to degrade. In certain embodiments, it can will be mixed at least one additive for the inhibitor peptides of the solid type dosage form of oral administration, The additive such as sucrose, lactose, cellulose, mannitol, trehalose, gossypose, maltitol, glucan, starch, fine jade Fat, alginates, chitin, chitosan, pectin, gum tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthesis Or semi synthetic polymer or glyceride.These dosage forms can also contain other types of additive, for example, inert diluents, Lubricant (such as magnesium stearate, p-hydroxybenzoate), preservative (such as sorbic acid, ascorbic acid, alpha-tocopherol), antioxidant Such as cysteine, disintegrant, adhesive, thickener, buffer, pH adjusting agent, sweetener, flavoring agent or aromatic.

It in a particular embodiment, can be with using compatible peroral dosage form or unit dose with the inhibitor peptides of the present invention Include the mixture and other disposable materials of inhibitor peptides and non-drug component or excipient, it is described disposable The material used can be considered as ingredient or packaging.Orally administered composition may include in liquid, solid and semisolid dosage form extremely Few one kind.In some embodiments, the peroral dosage form for including a effective amount of inhibitor peptides is provided, wherein the dosage form includes ball At least one of agent, tablet, capsule, gel, paste, potus, syrup, ointment and suppository.In some instances, this is provided The peroral dosage form of sample is designed and configured to realize sustained release of the inhibitor peptides in the small intestine and/or colon of object.

In one embodiment, including the combination of oral medication of the inhibitor peptides of the present invention includes to be designed to prolong The enteric coating that slow inhibitor peptides discharge in small intestine.In at least some embodiments, carried in delayed release medicine preparation For the pharmaceutical composition of inhibitor peptides and protease inhibitors (such as Aprotinin) comprising the present invention.In some instances, this hair Bright pharmaceutical composition includes the enteric coating that can be dissolved in about 5.0 or higher gastric juice of pH.In at least one embodiment In, the pharmaceutical composition comprising enteric coating is provided, the enteric coating includes the polymer with separable carboxyl, such as fiber The derivative of element, including hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate and cellulose acetate Trimellitate and similar cellulose derivative and other carbohydrate polymers.

In one embodiment, the pharmaceutical composition of the inhibitor peptides comprising the present invention is provided in enteric coating, Enteric coating is designed to protection pharmaceutical composition and is discharged it in the lower gastrointestinal tract system of object with controlled manner, and It is designed to avoid systemic side effects.In addition to enteric coating, inhibitor peptides of the invention can be encapsulated, coat, engage Or it associates in other ways in any compatible oral drug delivery system or component.For example, in some embodiments, it will The inhibitor peptides of the present invention are provided in lipid carrier system, and the system comprises polyalcohol hydrogel, nano particle, microballoons At least one of body, micelle and other lipid systems.

In order to overcome peptide to degrade in small intestine, some embodiments of the invention include the inhibitor peptides containing the present invention Aquogel polymer carrier system, thus aquogel polymer protect inhibitor peptides in small intestine and/or colon from protease Solution.The inhibitor peptides of the present invention can also be configured to and be designed to increase the dissolution kinetics of peptide and enhance intestinal absorption The compatible use of carrier system.These methods include using liposome, micelle and nano particle to increase the infiltration of the roads Tai GI.

One or more inhibitor peptides of various biological response systems and the present invention can also be combined to provide for mouth Take the medicament of delivering.In some embodiments, by the inhibitor peptides of the present invention with such as hydrogel and with hydrogen bond group Mucoadhesive polymers (for example, PEG, poly- (metering system) sour [PMAA], cellulose,Chitosan and alginic acid Salt) biological response system in combination use to provide the therapeutic agent for oral administration.Other embodiments include optimization or prolong The surface of the method for the drug residence time of long inhibitor peptides disclosed herein, wherein inhibitor peptides surface is modified with comprising logical Cross the mucoadhesive properties of hydrogen bond, the polymer of mucoprotein containing connection or/and hydrophobic interaction.The peptide molecule of these modifications Drug residence time increase can be shown in object, meet the desired character of the present invention.Moreover, target mucoadhesive system can To be combined with the receptor-specific on enterocyte and M cell surfaces, to further increase taking the photograph for the particle containing inhibitor peptides It takes.

Other embodiments include the method for the inhibitor peptides of the oral delivery present invention, wherein inhibitor peptides and infiltration are increased Strong agent combination is provided in object, and the penetration enhancers promote peptide to pass through intestines by increasing the osmosis on cell side or across cell The transhipment of mucous membrane.In Brayden, D.J., Mrsny, R.J., 2011.Oral peptide delivery：prioritizing It describes in the leading technologies.Ther.Delivery 2 (12), 1567-1573 and is controlled for oral delivery Treat the various penetration enhancers and method of agent.

In certain embodiments, pharmaceutical composition of the invention and preparation include the present invention inhibitor peptides and it is a kind of or A variety of penetration enhancers.The example of sorbefacient may include for example bile salt, aliphatic acid, surfactant (anion, sun from Son and non-anion), chelating agent, band-like (Zonular) OT, ester, cyclodextrin, dextran sulfate, azone, crown ether, EDTA, sucrose Ester and phosphatidyl choline.Although sorbefacient itself is not usually carrier, they are also widely combined with other carriers To improve oral administration biaavailability across the transhipment of intestinal mucosa by peptide and albumen.Substance of this kind can be used as excipient to be added To in preparation or be impregnated in with expected inhibitor peptides formed non-specific interaction.

It is confirmed as enhancing close connection infiltration and is generally acknowledged that the Dietary ingredient of safety (GRAS) and/or other naturally deposits Substance include such as asglycerides, fatty acyl carnitine, bile salt and medium chain fatty acid.The sodium salt of medium chain fatty acid (MCFAS) it is also considered as penetration enhancer.The MCFAS most studied extensively is sodium caprate, is caprate, and capric acid accounts for butterfat grade The 2-3% of aliphatic acid in point.So far, sodium caprate is mainly used as suppository formulations (Doktacillin^TM) in excipient to change The absorption of the ampicillin of kind rectum.Compared with sodium caprate, the Penetration Signature of another diet MCFAS, Sodium Caprylate (8 carbon) exist External display is lower.Sodium Caprylate and peptide medicament are mixed with other excipient in oil to prepare to generate enhancing infiltration Oily suspensions (OS) (Tuvia, S. et al., Pharmaceutical Research, Vol.31, No.8, the pp.2010- of property 2021(2014))。

For example, in one embodiment, penetration enhancers are combined with inhibitor peptides, during wherein penetration enhancers include At least one of chain fatty acid, long chain fatty acids, bile salt, amphiphilic surface activator and chelating agent.In certain embodiments In, Medium chain fatty hydrochlorate promotes to absorb by increasing the cell side permeability of enteric epithelium.In one embodiment, including N- The penetration enhancers of [(2-hydroxybenzoyl)) amino] Sodium Caprylate are used for forming weak noncovalent associations with the inhibitor peptides of the present invention, Wherein penetration enhancers are conducive to film transhipment and the further dissociation once reaching blood circulation.In another embodiment, The inhibitor peptides of the present invention are conjugated with oligomerization arginine, to increase the Premeabilisation of cells that peptide enters various cell types.In addition, In at least one embodiment, enhance in the inhibitor peptides of the present invention and the infiltration selected from cyclodextrin (CD) and dendritic macromole Non-covalent bond is provided between agent, wherein penetration enhancers reduce peptide aggregation and increase stability and the dissolving of inhibitor peptides molecule Property.

In certain embodiments, pharmaceutical composition or preparation include that the inhibitor peptides of the present invention and instantaneous permeability promote Agent (TPE).Penetration enhancer and TPE can be used for increasing oral administration biaavailability or inhibitor peptides.A reality of workable TPE Example be oily suspensions preparation, be dispersed with containing Sodium Caprylate and therapeutic agent powder (Tuvia, S. et al., Pharmaceutical Research, Vol.31, No.8, pp.2010-2021 (2014)).

In certain embodiments, pharmaceutical composition and preparation can include the inhibitor peptides of the present invention and one or more Sorbefacient, enzyme inhibitor or mucoadhesive polymers.

In a particular embodiment, the inhibitor peptides of the present invention are prepared in preparation medium, such as emulsion, lipid Body, microsphere or nano particle.

The inhibitor peptides treatment object with increased half-life period of the other embodiments of the present invention offer present invention Method.In one aspect, the present invention provides such inhibitor peptides：The inhibitor peptides are in vitro or in vivo (for example, when applying When with to people's object) there is half-life period of at least a few hours to one day, it is sufficient to once a day (q.d.) or twice daily (b.i.d.) dosage treatment effective amount.In another embodiment, inhibitor peptides have three days or longer half-life period, it is sufficient to one Zhou Yici (q.w.) dosage treatment effective amount.In addition, in another embodiment, inhibitor peptides have eight days or longer partly decline Phase, it is sufficient to (b.i.w.) or monthly dosage treatment effective amount biweekly,.In another embodiment, inhibitor peptides quilt Derivatization or modification so that it has longer half-life period compared with underivatized or unmodified inhibitor peptides.In another reality It applies in scheme, inhibitor peptides contain one or more chemical modifications to increase serum half-life.

When at least one in treatment as described herein or delivery system in use, the inhibitor peptides of the present invention can be with Pure form uses, or (in the presence of this form) is used with pharmaceutically acceptable salt form.

The inhibitor peptides of the present invention and daily total usage amount of composition can be by attending physicians in rational medical judgment It is determined in range.The particular treatment effective dose level of any specific object will depend on many factors, including：A) it is treated The severity of illness and illness；B) activity of specific compound used in；C) particular composition used in, the year of patient Age, weight, general health, gender and diet；D) administration time, administration method and the excretion of the specific inhibitor peptides used in Rate；E) duration treated；F) with specific inhibitor peptides combination used or drug used at the same time and medical domain Well known similar factor.

In a particular embodiment, people or the present invention of other mammalian hosts are applied to single dose or separate doses The amounts of every total daily dose of inhibitor peptides be for example daily 0.0001 to 300mg/kg weight or daily 1 to 300mg/kg bodies Weight.

The Noninvasive of enteritis detects

The part that the inhibitor peptides of the present invention can be used as non-invasive diagnostic program by microPET imagings is used for The detection of enteritis, assessment and diagnosis, wherein marking inhibitor peptides with chelation group or detectable label.In an embodiment In, inhibitor peptides are conjugated with bifunctional chelating agent.In another embodiment, inhibitor peptides are radiolabeled.Then will The inhibitor peptides of label are by oral administration or rectal administration is in object.In one embodiment, the inhibitor peptides of label are included in In drinking water.After inhibitor peptides intake, microPET imagings can be used to make the inflammation in the enteron aisle and alimentary canal of object Disease shows.

Inhibit the identification of the inhibitor peptides of IL-23 signal transductions

As described herein, in certain embodiments, compared to hyperkine R, inhibitor peptides of the invention and people IL-23R and/or rat IL-23R are preferentially combined.Compared with human IL-2 3R or rat IL-23R, hyperkine R is corresponding to small The about amino acid residue 315 of mouse IL23R albumen is to the region of about amino acid residue 340 (for example, amino acid region NWQPWSSPFVHQTSQETGKR contain other amino acid in) (see, e.g., Fig. 4).In a particular embodiment, peptide inhibits Agent is combined with the region of about amino acid 230 to the about amino acid residue 370 of human IL-2 3R.

The present invention provides the new method of the inhibitor (for example, inhibitor peptides) of identification IL-23R, based on identification and mouse IL-23R is compared to the preferential substance (for example, peptide) for combining human IL-2 3R or rat IL-23R.In certain embodiments, the side Method includes：(a) amount that candidate substances are combined with human IL-2 3R polypeptides or rat IL-23R polypeptides is measured；(b) candidate substances are measured The amount combined with hyperkine R polypeptides；And (c) by the amount of the combination human IL-2 3R polypeptides of measurement or rat IL-23R polypeptides And the amount of the combination hyperkine R polypeptides of measurement is compared, wherein if the combination human IL-2 3R polypeptides measured or rat The amount of IL-23R polypeptides is more than the amount in conjunction with hyperkine R polypeptides, then the candidate compound is the inhibitor of IL-23R. In specific embodiment, if the amount of the combination human IL-2 3R polypeptides or rat IL-23R polypeptides that measure is the combination mouse measured At least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 10 times, at least 20 times of the amount of IL-23R polypeptides, At least 30 times, at least 40 times, at least 50 times, at least 100 times, at least 200 times, at least 500 times or at least 100 times, then the time Compound is selected to be accredited as the inhibitor of IL-23R.In a particular embodiment, candidate compound is peptide.In specific embodiment In, the peptide is the peptide of one of formula described herein.In a particular embodiment, 3 polypeptide of human IL-2 or rat IL-23R are more Peptide separately includes the human IL-2 3R or rat IL-23R albumen or human IL-2 3R or rat IL-23R albumen by overall length of overall length Composition.In other embodiments, human IL-2 3R polypeptides are the segment of overall length human IL-2's 3R albumen, and it includes the pacts of human IL-2 3R 8 or more amino acid residues in amino acid residue 230 to the about region of amino acid residue 370.In other embodiments In, rat IL-23R polypeptides are the segment of overall length rat IL-23R albumen, and it includes the about amino acid residues 245 of rat IL-23R 8 or more amino acid residues in the about region of amino acid residue 385.

In another embodiment, the present invention provides the new method of the inhibitor (for example, inhibitor peptides) of identification IL-23R, , based on identification in conjunction with the substance in the region of human IL-2 3R or rat IL-23, the combination comes from mouse IL23R eggs due to existing for it White about amino acid residue 315 to about amino acid residue 340 other amino acid (for example, amino acid region NWQPWSSPFVHQTSQETGKR hyperkine R) is caused to be destroyed (see, e.g., Fig. 4).In certain embodiments, The method includes：(a) candidate substances are measured and fall into about amino acid residue 230 to the human IL-2 3R of about amino acid residue 370 The segment of polypeptide or with fall into about amino acid residue 245 to the segment knot of the rat IL-23R polypeptides of about amino acid residue 385 The amount of conjunction；(b) candidate substances are measured with negative control (for example, the negative control unrelated with human IL-2 3R or rat-IL-23R Peptide) combine amount；And (c) by the amount of the segment of combination human IL-2's 3R polypeptides of measurement or the segment of rat IL-23R polypeptides with The amount of the combination negative control of measurement is compared, wherein if the combination human IL-2 3R polypeptide fragments or rat IL-23R that measure The amount of polypeptide fragment is more than the amount in conjunction with negative control, then candidate compound is the inhibitor of IL-23R.In specific embodiment In, if the amount of the combination human IL-2 3R polypeptide fragments or rat IL-23R polypeptide fragments that measure is the combination negative control measured At least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 10 times, at least 20 times, at least 30 times of amount, extremely 40 times, at least 50 times, at least 100 times, at least 200 times, at least 500 times or at least 100 times few, then candidate compound is accredited as The inhibitor of IL-23R.In a particular embodiment, candidate compound is peptide.In a particular embodiment, the peptide is herein The peptide of one of described formula.In a particular embodiment, the segment of human IL-2 3R includes the about amino acid residue of human IL-2 3R At least eight, at least 12, at least 20, at least 50 or at least 100 amino in 230 to about 370 region of amino acid residue Sour residue or all amino acid residues.In other embodiments, the segment of rat IL-23R polypeptides includes rat IL-23R About amino acid residue 245 to the about region of amino acid residue 385 at least eight, at least 12, at least 20, at least 50 A or at least 100 amino acid residues or all amino acid residues.

Measuring the method that candidate compound is combined with IL-23 polypeptides is known in the art and includes but not limited in body The outer and binding analysis based on cell, including it is those of described herein.For example, can be by the candidate compound of label and combination The IL-23R polypeptides or negative control that the recombination of solid support generates are incubated and are persistently enough to allow to tie under certain conditions The time of conjunction, then by measure in conjunction with the amount of label associated of IL-23R polypeptides measure combination.

The Noninvasive of enteritis detects

The animal model of IBD

The present invention includes the model of Animal diseases, and the Animal diseases include diseases associated with inflammation and illness, such as inflammatory bowel Disease, for example, Crohn disease and colitis.As described in appended embodiment, develops diseases associated with inflammation and the several of illness move Object model.

In one embodiment, the present invention includes the energy for assessing candidate compound and inhibiting or reducing diseases associated with inflammation illness The method of power comprising：

(a) dextran sulfate sodium (DSS) for the amount for being enough to induce IBD is provided to rat；

(b) a certain amount of candidate compound is provided to rat；And

(c) amount of IBD symptoms present in the rat after DSS and candidate compound are provided is measured；

Wherein if the amount of the IBD symptoms measured in (c), which is substantially less than, is provided the DSS of the amount and a certain amount of control The amount measured in compound or control rats without peptide (for example, intermedium control), then candidate compound inhibit or reduce inflammation Property disease or illness.

In certain embodiments, DSS is provided about 5 to 12 days to rat, for example, about 9 days.In a particular embodiment, By provided to rat be freely exposed to containing DSS (for example, about 1% to about 10%DSS, about 2% to about 5%DSS or about 3% DSS drinking water) provides DSS to rat.In a particular embodiment, to rat provide about 5mg/kg to about 100mg/kg or The test compound of about 10mg/kg to about 50mg/kg or about 20mg/kg or about 30mg/kg.In a particular embodiment, Xiang great (for example, in drinking water) provides test compound to mouse by oral administration.In certain embodiments, DSS analyses are such as in appended implementation Progress described in example.

In another embodiment, the present invention includes the energy for assessing candidate compound and inhibiting or reducing diseases associated with inflammation illness The method of power comprising：

(a) 2,4,6- trinitrobenzene sulfonic acid (TNBS) of the amount for being enough to induce IBD are provided to rat；

(b) a certain amount of candidate compound is provided to rat；And

(c) amount of IBD symptoms present in the rat after TNBS and candidate compound are provided is measured；

Wherein if the amount of the IBD symptoms measured in (c) is substantially less than in the TNBS that provides the amount and a certain amount of right The amount measured according to compound or in the control rats without peptide (for example, intermedium control), then candidate compound inhibits or mitigation is scorching Disease property disease or illness.

In certain embodiments, about 10mg/kg to about 200mg/kg TNBS is provided to animal, for example, about 10mg/kg, About 20mg/kg, about 30mg/kg, about 40mg/kg, about 50mg/kg, about 60mg/kg, about 70mg/kg, about 80mg/kg, about 90mg/ Kg, about 100mg/kg, about 120mg/kg, about 150mg/kg or about 200mg/kg TNBS.In certain embodiments, TNBS exists In alcohol, for example, in the ethyl alcohol of 45%-50%.In a particular embodiment, by the straight enteral administrations of TNBS.In specific embodiment party In case, to rat offer about 5mg/kg to about 100mg/kg or about 10mg/kg to about 50mg/kg or about 20mg/kg or about 30mg/kg tests compound.In a particular embodiment, test chemical combination is provided to rat oral clothes (for example, in drinking water) Object.In certain embodiments, TNBS analyzes the progress as described in appended embodiment.

In a particular embodiment, in supply DSS or TNBS and candidate compound (or test compound or without compound) Later immediately measure IBD symptoms, or then for example initially supply DSS or TNBS and candidate compound (or test compound Or without compound) about 3 days later, measure IBD symptoms within 5 days or 9 days.In a particular embodiment, the IBD symptoms of measurement include body Mitigate percentage, stool consistency, quantitative hemoccult scores and colon weight again：Colon lengths are one or more than in. In certain embodiments, disease activity index (DAI) score and/or colon weight are used：Colon lengths ratio measures IBD symptoms, Wherein DAI scores are made of the grading from three parameters, and the parameter includes weight loss percentage, stool consistency and quantifies Hemoccult scores, and the maximum value of three units may be implemented.

In certain embodiments, anti-il-23 p 19 antibodies agent or the positive control of making comparisons will be neutralized.

In certain embodiments, in order to assess inflammatory response degree, such as the clinical sign of daily observation animal, Sign including weight loss percentage and loose stool or diarrhea.With DSS or TNBS be incubated a period of time (for example, 5 days, 6 days or 7 days) after, rat is put to death, and record the entire colon lengths and colon weight from caecum to rectum.It can be by treatment characteristic Unwitting virologist evaluates the severity of colitis.Other than colon wall thickness, it can be based on according to following table 19 The Traumatic Colon of 0-4 grades assessment substantially, and histopathological scores are determined based on parameter (table 20 and table 21) hereafter.

In certain embodiments, IBD symptoms are measured in three groups of rats, every group has at least 3 animals, for example, often Six animals of group, wherein three groups include：Medium, DSS or TNBS and DSS or TNBS and positive control (for example, with The sulfasalazine of 100mg/kg PO applications, QD).

Embodiment

Embodiment 1

The synthesis of peptide monomer

Using Merrifield solid phase synthesis techniques, synthesized in Protein Technology ' s Symphony multichannels The peptide monomer of the present invention is synthesized on instrument.Using HBTU (O- benzotriazole-N, N, N ', N '-tetramethyls-urea-hexafluoro-phosphate Salt), the coupling condition assembled peptide of diisopropylethylamine (DIEA).For certain amino acid, PyAOP (7- azepines benzos three are used Azoles -1- bases oxygroup) tripyrrole Wan Ji Phosphonium hexafluorophosphate) and DIEA coupling conditions.Rink Amide MBHA resins (100-200 Mesh, 0.57mmol/g) peptide that be used to have the ends C- amide, and the preloaded Wang trees with N- α-Fmoc protected amino acids The peptide that fat be used to have the ends C- acid.Prepare the coupling reagent (premixing HBTU and DIEA) of 100mmol concentration.Similarly, it makes The amino acid solution of standby 100mmol concentration.Identify that the peptide of the present invention inhibits based on medicinal chemistry optimization and/or phage display Agent, and screened to identify with those of excellent combination and/or rejection characteristic inhibitor peptides.

Assembling

Use the Symphony scheme assembled peptides of standard.Peptide sequence assembles as follows：By the resin in each reaction bottle (250mg, 0.14mmol) is washed twice with 4ml DMF, is then handled with the 4- methyl piperidines (Fmoc deprotection) of 2.5ml20% 10 minutes.Then resin is filtered, is washed twice with DMF (4ml), N- methyl piperidines is used in combination to handle again other 30 minutes.It will Resin is washed three times again with DMF (4ml), then adds 2.5ml amino acid and 2.5mlHBTU-DIEA mixtures.Frequently stirring After 45 minutes, resin is filtered and is washed (each 4ml) three times with DMF.For the typical peptide of the present invention, double couple crosslinking is carried out. After completing coupling reaction, resin is washed (each 4ml) three times with DMF before carrying out next round amino acid couplings.

Cultural care is to form alkene

Resin (100 μm of ol) is washed into (3 × 1 minutes) with 2ml DCM, is then urged with the 2ml 6mM Grubbs first generation Solution (4.94mg ml-1 of the agent solution in DCE；Be substituted by 20mol% about resin) processing before, washed with 2ml DCE It washs (3 × 1 minutes).Before being discharged, solution is refluxed overnight under a nitrogen (12 hours).Resin is washed three times with DMF (each 4ml)；It is washed with DCM (4ml) before being dried and being cut.

Cutting

After peptide is completed, by with cutting reagent such as reagent K (82.5% trifluoroacetic acid, 5% water, 5% thiophenyl Methane, 5% phenol, 2.5%1,2- dithioglycols) processing, by peptide under resin cutting.Cutting reagent can successfully by peptide from Resin cutting is lower and cuts all remaining Side chain protective groups.

The peptide of cutting precipitates in cold ether, is then washed twice with ether.Filtrate is poured out, addition second etc. The cold ether of part, and repeat above procedure.Thick peptide is dissolved in acetonitrile: in the solution of water (7: 3, contain 1%TFA) and being filtered. Then, before purification, the matter of linear peptides is verified using electrospray ionization mass spectrometry (ESI-MS) (Micromass/Waters ZQ) Amount.

Via the formation of the disulfide bond of oxidation

Follow general Fmoc-SPPS programs, Rink Amide-MBHA assembled on resin containing free mercaptan (such as DiPen peptide).By with cutting reagent (90% trifluoroacetic acid, 5% water, 2.5%1,2- dithioglycols, 2.5% triisopropyl Silane) processing, by peptide under resin cutting.The peptide of cutting is precipitated in cold ether, is then washed twice with ether. Filtrate is poured out, adds the cold ether of the second equal portions, and repeat above procedure.Thick peptide is dissolved in acetonitrile: water (7: 3, contain 1% TFA it in solution) and filters, obtains the desired thick peptide for not aoxidizing peptide.

The rough cutting peptide that X4 and X9 is Cys, Pen, hCys, (D) Pen, (D) Cys or (D) hCys is dissolved in 20ml water: In acetonitrile.Then the acetic acid of the iodine containing saturation is added dropwise under stiring, until yellow continues.Solution is stirred 15 minutes, and With analytic type HPLC and LCMS monitoring reaction.When the reactions are completed, solid ascorbic acid is added, until solution is clarified.Then lead to Cross following purification solvent mixture：Be diluted with water first, be then loaded into reversed-phase HPLC machine (Luna C18 supports, 10u, 100A, mobile phase A：Water containing 0.1%TFA, Mobile phase B：Acetonitrile (ACN) containing 0.1%TFA, gradient since 5%B, And became 50%B after 60 minutes, flow velocity is 15ml/ minutes) on.Then to the fraction containing pure products on freeze drier It is freeze-dried.

The formation of lactam bond

100mg rough cuttings peptide (about 0.12mmol) is dissolved in 100ml anhydrous methylene chlorides.Add HOBt (1- hydroxyls Base benzotriazole hydrate) (0.24mmol, 2 equivalents), then adding DIEA (n,N-diisopropylethylamine), (1.2mmol, 10 work as Amount) and TBTU (O- (benzotriazole -1- bases)-N, N, N ', N '-tetramethylureas tetrafluoroborate) (0.24mmol, 2 equivalents). The mixture was stirred overnight, and passes through HPLC following responses.When the reactions are completed, dichloromethane is evaporated, with water and acetonitrile Dilution, is then loaded into reversed-phase HPLC machine (Luna C18 supports, 10u, 100A, mobile phase A：Water containing 0.1%TFA, stream Dynamic phase B：Acetonitrile (ACN) containing 0.1%TFA, gradient become 50%B since 5%B, and after 60 minutes, and flow velocity is 15ml/ minutes) on.Then the fraction containing pure products is freeze-dried on freeze drier.

The formation of triazole key

At room temperature, by the purified peptide containing related amino acid alkynes and azide pH 7.4 phosphate/MeOH (1mg/2ml) is stirred in (2: 1).Add CuSO45H₂O (10 equivalent) and sodium ascorbate (10 equivalent), and by mixture It is stirred 36 hours in room temperature.MeOH is removed, and so that solution is acidified to pH 3 with 1%TFA aqueous mixtures.Then it is being loaded to HPLC is for filtering solution before the purifying of peptide.

The formation of thioether bond

Follow general Fmoc-SPPS programs, Rink Amide-MBHA assembled on resin containing free mercaptan (such as ) and the peptide of hSer (OTBDMS) Cys.Chlorination passes through the PPh in DCM₃(10 equivalent) and Cl₃CCN (10 equivalent) processing Resin 2 hours carries out.By the way that with cutting reagent, (90% trifluoroacetic acid, 5% water, 2.5%1,2- dithioglycols, 2.5% 3 is different Propyl silane) processing, by peptide under resin cutting.The peptide of cutting is precipitated in cold ether, is then carried out twice with ether Washing.Filtrate is poured out, adds the cold ether of the second equal portions, and repeat above procedure.Thick peptide is dissolved in acetonitrile: water (7: 3, Containing 1%TFA) solution in and filter, obtain desired not being cyclized thick peptide.

There to be free mercaptan (for example, Cys, Pen, hCys, (D) Pen, (D) Cys on X4 and X9 or the positions X9 and X4 Or (D) hCys) and the thick peptide of alkyl halide (hSer (Cl)) be dissolved in the 0.1M TRIS buffer solutions of pH8.5.Make cyclisation in room temperature It is lower to occur overnight.Then pass through following purification solvent mixture：It is diluted twice with water first, is then loaded into reverse phase HPLC machines (Luna C18 supports, 10u, 100A, mobile phase A：Water containing 0.1%TFA, Mobile phase B：Containing 0.1%TFA's Acetonitrile (ACN), gradient become 50%B since 5%B, and after 60 minutes, and flow velocity is 15ml/ minutes) on.Then it is freezing The fraction containing pure products is freeze-dried on drying machine.

The formation of selenide key

It will be dissolved in the pH 5.5 containing DTT in the X4 and X9 thick peptide containing the shielded selenoaminoacid of mercaptan and alkyl halide 0.1M sodium phosphate buffers (40 equivalent) in.Cyclisation is set to occur at room temperature after 24 hours.Then solution is diluted with water Twice, final cyclisation peptide is purified using RP-HPLC, selenide is provided.

The formation of two selenium keys

Diselenide precursor is dissolved in the 0.1M phosphate buffers of pH 6.0 and aqueous isopropanol containing DTT, and (40 work as Amount) in, and by reaction mixture in 37 DEG C of incubations.After 20 hours, other DTT (10 equivalent) is added into reactant. After 32 hours in total, cyclization then is diluted with twice of water, and final cyclisation peptide is purified using RP-HPLC, Diselenide is provided.

Purifying

Analytic type reversed-phase high performance liquid chromatography (HPLC) is on Gemini C18 columns (4.6mmx250mm) (Phenomenex) It carries out.Semi-preparative reverse-phase HPLC is in 10 μm of C18 columns (22mmx250mm) (Phenomenex) of Gemini or 10 μ of Jupiter It is carried out on m, 300A DEG C of 18 columns (21.2mmx250mm) (Phenomenex).Use linear gradient (flowing of the buffer solution B in A Phase A：Water containing 0.15%TFA, Mobile phase B：Acetonitrile (ACN) containing 0.1%TFA), with 1mL/ minutes flow velocitys (analytic type) and 15mL/ minutes flow velocitys (preparative) realize separation.Use linear gradient (mobile phase A of the buffer solution B in A：Containing 0.15% The water of TFA, Mobile phase B：Acetonitrile (ACN) containing 0.1%TFA), with 1mL/ minutes flow velocitys (analytic type) and 15mL/ minutes Flow velocity (preparative) realizes separation.

The activation of connector and dimerization

Peptide monomer subunit is connected to form peptide dimer inhibitor as described below.

Small-scale DIG connectors activation procedure：5mL NMP are added to diacid containing IDA (304.2mg, 1mmol), N- hydroxyls In base succimide (NHS, 253.2mg, 2.2 equivalent, 2.2mmol) and the vial of stirring rod.It is stirred at room temperature mixed Object is closed so that solid raw material fully dissolves.Then to mixture add N, N '-dicyclohexylcarbodiimides (DCC, 453.9mg, 2.2 equivalents, 2.2mmol).Occur precipitating in 10 minutes and futher stirs reaction mixture at room temperature Overnight.Then reaction mixture is filtered to remove the dicyclohexylurea (DCU) of precipitation.Before for dimerization, it will live Change connector to be stored in sealed vial.The nominal concentration for activating connector is about 0.20M.

For the dimerization using PEG connectors, pre-activate step it is not related to.Using commercially available preactivated difunctional PEG connectors.

Dimerization program：2mL anhydrous DMFs are added in the bottle containing peptide monomer (0.1mmol).With DIEA by the pH of peptide It is adjusted to 8~9.Then activation connector (IDA or PEG13, PEG 25) is added to monomer solution (relative to monomer to work as 0.48 Amount, 0.048mmol).Reaction mixture is stirred at room temperature one hour.The complete of dimerization is monitored using analytic type HPLC At.The time that dimerization is completed changes according to connector.After the reaction was completed, peptide precipitated in cold ether and from The heart.Abandon the ether layer on upper layer.Settling step is repeated twice.Then use reversed-phase HPLC (Luna C18 supports, 10u, 100A, mobile phase A：Water containing 0.1%TFA, Mobile phase B：Acetonitrile (ACN) containing 0.1%TFA, 15%B and after 60 minutes become For the gradient of 45%B, flow velocity 15ml/ minutes) the thick dimer of purifying.Then on freeze drier to the fraction containing pure products into Row freeze-drying.

Embodiment 2

Peptide inhibits the characterization that Interleukin-23 is combined with Interleukin-23 receptor

The optimization of peptide is carried out to identify that (for example, IC50 ＜ 10nM) is active at low concentrations while stomach and intestine (GI) are presented surely The inhibitor peptides of qualitative IL-23 signal transductions.As described below, certain peptides are tested and inhibits IL-23 and people IL- to identify 23R is combined and is inhibited the peptide of IL-23/IL-23R functional activities.The peptide tested includes containing various different cyclisation chemical substances The peptide of (including such as cyclic amides (side chain cyclisation)) peptide containing disulfide bond and contains sulphur between such as two Pen residues The peptide of ehter bond.The inhibitor peptides of the present invention include but not limited to the peptide with any structure described herein.In addition, of the invention Inhibitor peptides include have it is those of identical as the amino acid sequence of peptide described herein or structure, without with phase Same or any ends N- or the ends C- " sealing end " group, e.g., for example, Ac or NH₂。

Being analyzed as follows of measuring that peptide activity carried out is described, and results of these analyses are provided in table E3A-E3H, table In E4A and table E4B, table E5A-E5C, table E6, table E7 and table E8.People ELISA indicates that IL23-IL23R as described below is competitive Binding analysis, rat ELISA indicate the analysis of rat IL-23R competitive binding ELISAs and pStat3HTRF as described below Indicate DB cell IL-23R pSTAT3 cell analysis as described below.Peptide described in table E3B-E3E is via two in these peptides The disulphide bridges that are formed between a cysteine and be cyclized.As indicated, the peptide described in table E3F via junction portion or passes through inside Cysteine portion dimerization.Peptide described in table E4A and E4B via these peptides respectively present in two Pen residues cyclisation. Peptide described in table E5A is cyclized via the thioether bond between instruction amino acid residue.Table E5B provides the example of description thio-ether cyclization Property structure, indicated by term " ring " in table, followed by the ring region for adding square brackets.Peptide dimer shown in table E5C Monomelic subunit as shown by term " ring " be cyclized and the connector shown in be connected to each other.Peptide shown in table E6 via The cultural care of shown residue is cyclized.Table E7 provides two example arrangements of the description via cyclic amides side chain cyclisation, And the peptide in the table is pressed term " ring " and is cyclized as shown.Table E8 descriptions are cyclized via cysteine residues and Pen residues Peptide.

The inhibitor peptides of the present invention include the cyclic versions and non-cyclizing form of peptide shown in this article.For certain peptides, Residue A bu exists in the position of instruction, and in the other embodiments for being related to non-cyclizing form, Abu is referred to alternatively as hSer (Cl) or high Ser residues.

IL23-IL23R competitive binding ELISAs

It willThe IL23R_huFC packets in the 4HBX plates holes 50ng/ are merged in 4 DEG C of overnight incubations.By hole PBST Washing four times is closed 1 hour in room temperature with the PBS containing 3% skimmed milk, and is washed again with PBST four times.Exist to the addition of each hole The serial dilution of the test peptides and IL-23 of diluted final concentration of 2nM in analysis buffer (PBS for containing 1% skimmed milk), and And in incubation at room temperature 2 hours.After device to hole is washed, pass through the goat with the diluted holes 50ng/ in analysis buffer Anti- p40 polyclonal antibodies (R＆D Systems #AF309) detect the IL-23 of combination in being incubated at room temperature 1 hour.Hole is used PBST is washed four times again.Then secondary antibody is added (with 1: the 5000 anti-goat of donkey conjugated diluted HRP in analysis buffer IgG (Jackson ImmunoResearch Laboratories #705-035-147)), and in incubation at room temperature 30 minutes. As above plate is finally washed.With TMB one pack system HRP films substrate (TMB One Component HRP Membrane Substrate) signal is made to show, be quenched with 2M sulfuric acid and read under 450nm using spectrophotometry.It is surveyed from these data The IC50 values of fixed various test peptides are shown in table E3A-E3H, table E4A and 4EB, table E5A-E5C, table E6, table E7 and table E8.

Rat IL-23R competitive binding ELISAs

The rat IL-23R_huFC packets in the analysis plates holes 300ng/ are merged in 4 DEG C of overnight incubations.Device to hole is washed, It closes and washs again.The serial dilution of the test peptides and IL-23 of final concentration of 7nM is added to each hole, and in incubation at room temperature 2 Hour.After device to hole is washed, with the anti-p40 polyclonal antibodies of goat, then knot is detected with the donkey anti goat igg that HRP is conjugated The IL-23 of conjunction.Signal is set to show and be quenched with 2M sulfuric acid with TMB one pack system HRP film substrates.From the various surveys of these data determinations The IC50 values of examination peptide are shown in table E3G, table E3H, table E4A, table E4B, table E5B, table E5C and table E8.

DB cell IL23R pSTAT3 cell analysis

IL-23 is supporting and is maintaining to play main function in Th17 differentiation in vivo.The process is considered mainly passing through signal It transduces and is mediated with activating transcription factor 3 (STAT3), the phosphorylation of STAT3 leads to RORC and proinflammatory IL- (generate pSTAT3) 17 up-regulation.When being stimulated with IL-23 in the presence of testing compound, the DB which has checked expression IL-23R is thin PSTAT3 in born of the same parents is horizontal.It will be in RPMI-1640 culture mediums (the ATCC #30- for being supplemented with 10%FBS and 1% glutamine 2001) the DB cells (ATCC #CRL-2289) cultivated in are seeded in 5X10E5 cells/well in tissue culturing plates with 96 hole.To The test peptides of final concentration of 0.5nM and the serial dilution of IL-23 are added in each hole, and at 37 DEG C, 5%CO₂Moistening culture It is incubated 30 minutes in case.Using Cisbio HTRF pSTAT3 cell analysis kits, according to the two plate analysis schemes of manufacturer, Detect the variation of phosphorylation-STAT3 levels in cell lysate.It is aobvious with absolute value or range from the IC50 values of these data determinations It is shown in table E3E, table E3G, table E3H, table E4A, table E4B, table E5B, table E5C and table E8.Not shown place, undetermined data.

Table E3A. illustratively non-cyclic peptide and activity

The exemplary peptides of table E3B. motifs containing CXXXXC of IC50 ＞ 1uM in IL23-IL23R competitive binding ELISAs

The motif containing CXXXXC that table E3C. IC50 in IL23-IL23R competitive binding ELISAs are 500nM to 1000nM Exemplary peptides

Table E3D. in IL23-IL23R competitive binding ELISAs the motif containing CXXXXC of IC50 ＜ 500nM it is exemplary Peptide

The IC50 of the exemplary peptides of the active motifs containing CXXXXC of table E3E.

*=＜ 10nM；*=10-25nM * * *=25-100nM, * * * *=100-1000nM, * * * * *=1000-10, 000nM。

The IC50 of table E3F. exemplary peptides dimers

The IC50 of exemplary peptides of the table E3G. containing CXXWXCXXXXX- [(D) Lys] motif

The IC50 of the exemplary peptides of table E3H. motifs containing CXXWXCXXXX

The illustrative examples of the dimer of peptides of the table E4A. containing Ac- [Pen]-XXWX- [Pen]-XXXX motifs and analog IC50

*=＜ 10nM；*=10-25nM, * * *=25-100nM, * * * *=100-1000nM, * * * * *=1000-10, 000nM

The IC50 of exemplary peptides of the table E4B. containing Ac- [Pen]-XXWX- [Pen]-XXXX motifs and analog

The IC50 of table E5A. exemplary peptides inhibitor (thioether)

The IC50 of table E5B. exemplary peptides inhibitor (thioether)

Ac- rings-[[Abu] XXWXC]-[Phe (4-OMe)]-[2-Nal]-XXX-NH₂

=＜ 10nM；*=10-25nM * * *=25-100nM, * * * *=100-1000nM, * * * * *=＞ 1000nM.

The IC50 of the exemplary thioether peptide dimer of table E5C. synthesis

*=＜ 10nM；*=10-25nM * * *=25-100nM, * * * *=100-1000nM, * * * * *=＞ 1000nM.

The exemplary thioether peptides of table E5D.

*=≤ 1nM；*=1nM-10nM；* *=10nM-100nM

The IC50 of table E6. inhibitor peptides (cultural care)

The IC50 of exemplary peptides of the table E7. containing cyclic amides (side chain cyclisation)

Exemplary peptides of the table E8. containing Ac- [Pen]-XXWXXXXXX motifs and Ac-XXXWX- [Pen]-XXXX analogs IC50

The active SAR of the inhibitor peptides tested analysis shows, CXXXXC disulphide is related to high activity.Two Trp residues and Phe residues are also related to high activity, it should be appreciated that these amino acid can use similar homologue to be easy to exchange (for example, 1-Nal is substituted by Trp and/or Phe is substituted by Tyr).In addition, statistics indicate that, one or more alkali at the ends C- The presence of property residue is related to high activity.Moreover, His-9 can be replaced by Arg or another homologues and be maintained or improve activity.Under The diagram in face provides a kind of exemplary consensus sequence, shows and the relevant certain residues of high activity.

Embodiment 3

Stability of the inhibitor peptides under simulated intestinal fluid (SIF), simulate the gastric juice (SGF) and Redox Condition

The stomach of the inhibitor peptides to evaluate the present invention is studied in simulated intestinal fluid (SIF) and simulate the gastric juice (SGF) Stability.In addition, being studied the oxidation-reduction stability of the inhibitor peptides to assess the present invention.

By adding 6.8g potassium dihydrogen phosphates and 10.0g pancreatin preparation SIF to 1.0L water.It, will using NaOH after dissolving PH is adjusted to 6.8.The DMSO liquid storages (2mM) for testing compound are prepared first.The DMSO solution of equal portions is assigned to 6 lists In only pipe, often pipe contains 0.5mL SIF, is preheated to 37 DEG C.Final test compound concentration is 20 μM.It is held in experiment In continuous period, bottle is maintained at desk-topIn.(0,5,10,20,40,60 or 360 minute each time point Or 24 hours), to an acetonitriles of the bottle addition 1.0mL containing 1% formic acid to terminate reaction.Sample is stored in 4 DEG C until reality Test end.After last point in time sampling, pipe is mixed, is then centrifuged 10 minutes in 3,000rpm.Remove the upper of equal portions Clear liquid is diluted to 1: 1 in the distilled water of containing the internal standard, and is analyzed by LCMS/MS.Based on test compound and interior target Remaining percentage of the peak area response than calculating each time point.Time 0 is set as 100%, and calculates and owns relative to the time 0 Subsequent time point.First-order exponential decay equation is fitted to by using Graphpad to calculate half-life period.It is steady in SIF analyses It is qualitative to be shown in table E9 and table E10.

By adding 20mg NaCl, 32mg porcine pepsin (MPBiochemicals, catalogue to 10ml water： 02102599) and 70 μ l HCl prepare SGF (final pH=2).By equal portions SGF (each 0.5ml) in 37 DEG C of preheatings.It is anti-in order to originate It answers, 1 μ l peptides liquid storage (10mM, in DMSO) is added to 0.5ml SGF and is sufficiently mixed so that final peptide concentration is 20 μM.It will be anti- Object slight vibration at 37 DEG C is answered to be incubated.In each time point (0,15,30,60 minute), 50 μ l equal portions are removed, and add it to In acetonitriles of the 200ul containing 0.1% formic acid to quench the reaction.Sample is stored in 4 DEG C until testing to terminate, and in 10,000rpm Centrifugation 5 minutes.The supernatant for removing equal portions, is diluted to 1: 1 in the distilled water of containing the internal standard, and analyzed by LCMS/MS. Remaining percentage based on test compound with interior target peak area response than calculating each time point.Time 0 is set as 100%, And calculate all subsequent time points relative to the time 0.First-order exponential decay equation is fitted to by using Graphpad to count Calculate half-life period.Stability in SGF analyses is shown in table E9 and table E10.

Exemplary peptides of the table E9. containing Ac- [Pen]-XXWX- [Pen]-XXXX motifs and analog are at simulated intestinal fluid (SIF) With the stability in simulate the gastric juice (SGF)

The matrix that § is used is 100 times of dilutions of standard SIF concentration

*=＞ 360 minutes；*=180-360 minutes；* *=120-180 minutes；60-120 points of * * *=＜ Clock；* * * *=＜ 60 minutes

The exemplary peptides of table E10. Sulfide-containing Hindereds motif and analog are in simulated intestinal fluid (SIF) and simulate the gastric juice (SGF) Stability

For each peptide tested, by adding 10mMs of the 5 μ l in DMSO to 1ml 100mM Tris-Cl, pH 7.5 Peptide liquid storage (final peptide concentration is 50 μM) carries out DTT stability analyses.At 0 minute, it is fresh to add 5 μ l to the incubation tube containing peptide The 100mM DTT solution of defrosting so that a concentration of 0.5mM of final DTT.By reactant in incubation at room temperature.Until 120 minutes Different time points (20 minutes, 40 minutes, 80 minutes, 120 minutes), remove 50 μ l equal portions, by add 10 μ l 5M acetic acid quench It goes out reaction.In order to measure the disappearance of parent's peptide, by reversed-phase HPLC and in sample (30 μ that are quenched of UV spectrophotometric analysis of 220nm l).Remaining oxidation fractions are mapped relative to the time, and are fitted to first-order exponential decay equation calculation half by using Excel It declines the phase.The result of these researchs is shown in table E11.120 minutes peptides of half-life period ＞ are considered as stable.

Stability of the table E11. exemplary peptides in DTT analyses

*=10-120 minutes

Embodiment 4

The cross reactivity of inhibitor peptides

The amino acid of the extracellular domain of human IL-2 3R is respectively with macaque IL-23R, rat IL-23R and hyperkine R 95%, 77% and 70% is same.It is not deposited in people, mouse, chimpanzee, dog and Niu Shouti it is interesting that mouse receptor contains 21 residues insertion.These other amino acid are located in such region：The region is considered as human IL-2 3R The place combined with IL-23.

It is certain by elisa assay in order to identify the inhibitor peptides with the IL-23R cross reactions of species in addition to a person Inhibitor peptides inhibit the ability of human IL-2 3R, macaque IL-23R, rat IL-23R and hyperkine R.With about human IL-2 3R and The observation of sequence difference between hyperkine R is consistent, and in hyperkine R ELISA, the peptide antagonists tested are shown Lack inhibitory activity or the very weak inhibitory activity of display (referring to table E12).In contrast, the antagonist tested so far The comparable effect for rat receptor, and the slightly small activity for macaque receptors is presented.

The various biologies point that the effect for measuring IL-23R antagonists, cross reactivity and selectivity are carried out are described below Analysis.

The analysis of the selectivity of specific IL-23R antagonists

1 ELISA of people IL-12R β

It is coated with analysis plates with the people IL-12R β 1_huFC in the holes 100ng/ and in 4 DEG C of overnight incubations.Hole is washed, It closes and washs again.The serial dilution of the test peptides and IL-23 of final concentration of 2.5nM is added to each hole, and in room temperature It is incubated 2 hours.After hole is washed, with the anti-p40 polyclonal antibodies of goat, the subsequent anti-mountain of donkey by being conjugated with HRP The IL-23 that sheep IgG detections combine.Signal is set to show and be quenched with 2M sulfuric acid with TMB one pack system HRP film substrates.

Hyperkine R competitive binding ELISAs

It is coated with analysis plates with the hyperkine R_huFC in the holes 50ng/ and in 4 DEG C of overnight incubations.Hole is washed, is sealed It closes and washs again.The serial dilution of the test peptides and IL-23 of final concentration of 4nM is added to each hole, and in incubation at room temperature 2 Hour.After hole is washed, with the anti-p40 polyclonal antibodies of goat, the subsequent donkey anti goat igg by being conjugated with HRP Detect the IL-23 combined.Signal is set to show and be quenched with 2M sulfuric acid with TMB one pack system HRP film substrates.

Rat IL-23R competitive binding ELISAs

It is coated with analysis plates with the rat IL-23R_huFC in the holes 300ng/ and in 4 DEG C of overnight incubations.Hole is washed, It closes and washs again.The serial dilution of the test peptides and IL-23 of final concentration of 7nM is added to each hole, and is incubated in room temperature It educates 2 hours.After hole is washed, with the anti-p40 polyclonal antibodies of goat, the subsequent anti-goat of donkey by being conjugated with HRP The IL-23 that IgG detections combine.Signal is set to show and be quenched with 2M sulfuric acid with TMB one pack system HRP film substrates.

Macaque IL-23R competitive binding ELISAs

It is coated with analysis plates with the macaque IL-23R_huFC in the holes 50ng/ and in 4 DEG C of overnight incubations.Hole is washed, is sealed It closes and washs again.The serial dilution of the test peptides and IL-23 of final concentration of 2nM is added to each hole, and in incubation at room temperature 2 Hour.After hole is washed, with the anti-p40 polyclonal antibodies of goat, the subsequent donkey anti goat igg by being conjugated with HRP Detect the IL-23 combined.Signal is set to show and be quenched with 2M sulfuric acid with TMB one pack system HRP film substrates.

The cross reactivity of table E12. exemplary peptides inhibitor

+++ indicate 0-250nM

++ indicate 251-1000nM

+ indicate 1001-10,000nM

Indicate ＞ 25,000nM

Embodiment 5

NK cell analysis

Natural kill (NK) cell (Miltenyi that will be purified from the human peripheral of healthy donors by Solid phase Biotech, Cat # 130-092-657) there are the complete trainings of 25ng/mL IL-2 (RnD, Cat # 202-IL-010/CF) Support culture in base (RPMI 1640 containing 10%FBS, L-Glutamine and Pen .- Strep).After 7 days, cell is carried out It centrifuges and is resuspended in complete medium with 1E6 cell/mL.By the recombinant il-2 3 and 10ng/mL of predetermined EC50 to EC75 IL-18 (RnD, Cat # B003-5) is mixed with the peptide of various concentration, and is added to the NK cells of 1E5, every hole cell inoculation In.After 20 to 24 hours, the IFN γ in supernatant is quantified using Quantikine ELISA (RnD, Cat # DIF50).

IC50 (NK cell analysis) of the table E13. exemplary peptides inhibitor in primary cell line

*=＜ 25nM

IC50 (the NK cells point of exemplary peptides of the table 14. containing Ac- [Pen]-XXWX- [Pen]-XXXX motifs and analog Analysis)

*=＜ 10nM；*=10-25nM

Embodiment 6

The bioanalysis of inhibitor peptides characterizes

The effect of certain inhibitor peptides is measured using various bioanalysis researched and developed for this purpose and described below Power, cross reactivity and selectivity.

Rat spleen cells are analyzed

The new analysis researched and developed is that rat spleen cells are analyzed.The analysis have checked in the presence of testing compound with The level of IL-17A in the post-stimulatory activation rat spleen cells of IL-23.

In short, 96 holes for being seeded in the complete medium containing IL-1 β from the splenocyte of rat fresh separated are organized In culture plate.The serial dilution of compound and rat IL-23 will be tested with together in EC50 to the final concentration between EC80 values It distributes to each hole；Then by plate in 37 DEG C, 5%CO₂Humidified incubator in be incubated 3 days.It is detected in supernatant using ELISA The variation of IL-17A levels.

Rat colitis model：9 days drinking water containing 3%DSS

There are a large amount of evidences in the literature and supports cause of the IL-23/IL-23R signal transductions in the animal model of colitis Disease effect.For IL-23 ligands, which has been shown in a variety of models, including IL-10^-/-Spontaneous colitis model, liver spiral shell Colitis model that bacillus (Helicobacter hepaticus) drives, congenital colitis models of anti-CD40 and chronic CD45RB^{It is high}CD4⁺T- cell transfer models.For IL-23 receptor, the demand for colitis development have been shown in by DSS or by The acute colitis model and chronic CD45RB of anti-CD40 inductions^{It is high}CD4⁺T- cell transfer models.Due to the present invention it is certain Inhibitor peptides not with the IL-23 receptor cross reaction from mouse but identify the IL-23 receptor from rat, so research and development with The rat model of the relevant IBD of IL-23 accesses.

In the model, by being freely exposed to the drinking water 9 days containing 3%DSS, the inducing colitis in SD rats.Than Compared with three seminar (n=6 rat/group)：Medium, 3%DSS and 3%DSS and positive control (are applied with 100mg/kg PO Sulfasalazine, QD) disease activity index (DAI) score and colon weight：Colon lengths ratio.DAI scores are by coming from three The grading of a parameter forms, and the parameter includes weight loss percentage, stool consistency and quantifies hemoccult scores, and The maximum value of three units may be implemented.Notable raised DAI scores were presented in the animal for being exposed to DSS from preceding 4th day (compared with intermedium control), (the 9th day) DAI values reach about 2.5 peak value at the end of research.With positive control (willow nitrogen sulphur pyrrole Pyridine) processing is exposed to the rat of DSS that disease severity is made to reduce (compared with individual DSS) from the 5th day.For with without willow For the diseased n animal of the DSS inductions of nitrogen sulphur pyridine processing, in colon weight：The difference observed in the final ratio of colon lengths It is significant.

Isolated activity and stability

Two kinds of peptides (compound A and compound B) of selection are used for further biological study (being shown below).One kind containing sulphur Ehter bond, another kind contain Pen-Pen disulfide bond.Provided herein is the activity of two kinds of compounds, selective and in vitro stability characteristics.

The analysis of the selectivity of inhibitor peptides includes being generated in people IL-12Rb1 ELISA and the human PBMC of measurement PHA activation IL-12, the analysis is described briefly below.

1 ELISA of people IL-12R β

It is coated with analysis plates with the people IL-12Rb1_huFC in the holes 100ng/ and in 4 DEG C of overnight incubations.Hole is washed, It closes and washs again.The serial dilution of the test peptides and IL-23 of final concentration of 2.5nM is added to each hole, and in room temperature It is incubated 2 hours.After hole is washed, with the anti-p40 polyclonal antibodies of goat, the subsequent anti-mountain of donkey by being conjugated with HRP The IL-23 that sheep IgG detections combine.Signal is set to show and be quenched with 2M sulfuric acid with TMB one pack system HRP film substrates.Provided herein is Data from these analyses.

IFN γ is generated by IL-12 in the human PBMC of PHA activation

The analysis has checked the ability that IFN γ albumen is generated in IL-23R antagonists and in the human PBMC of IL-12 stimulations.It is right The special IL-23R inhibitor peptides of IL-23/IL-23R accesses are expected not changing the level of generated IFN γ.In this analysis Test compound A and compound B, Fig. 2, which is provided, to be shown under most Particle density of test them and do not change generated IFN The figure of γ levels.

Compound A

Compound B

Activity in vivo

It is induced by raising female Sprague Dawley rats with 3% (wt/vol) DSS being dissolved in drinking water Acute colitis.Start on the same day with DSS lasting nine days, compound A or B is applied by oral administration three times a day with 20mg/kg or 30mg/kg With.Compound A in 30mg/kg three times a day peritonaeum also to apply.Anti-il-23 p 19 antibodies agent of making comparisons is neutralized, and is being opened Beginning DSS on the same day and the 5th day later in 4mg/kg peritonaeums to apply.For the colitis quantitatively with clinical activity, daily Measure the disease activity index (DAI) of each animal, the average value as three parameters：Changes of weight (grade 0-3), excrement are thick (grade 0-3) and hemoccult blood (grade 0-3) are spent, as shown in table E15.In ptomatopsia, remove from caecum to rectum Entire colon.The length for measuring colon is rinsed with PBS to remove excreta, is weighed and longitudinally slit to measure macroscopical score.With The grade of 0-3 scores to the visible damage of colon, as shown in table E16.

Table E17 is shown, at the 7th day, compared with medium processing group, is significantly improved with compound A and the B processing carried out DAI scores.Fig. 1 shows the result of the DAI values from the 7th day.In addition, it was further observed that the ratio between colon weight and colon lengths and colon Macroscopical score substantially reduce (Fig. 3).The mitigation for the inflammation observed with the peptide delivered by oral administration with by neutralizing anti-IL23p19 The effect that monoclonal antibody is observed is similar.Statistical significance analysis is compared with medium processing group, and is used Student T- examines (GraphPad Prism) to be measured.Difference is registered as significant * p ＜ 0.05, * * p ＜ 0.01, * * * p ＜ 0.001, * * * * p ＜ 0.0001.

The scoring of table E15. disease activity index

Score	Changes of weight percentage	Stool consistency	Hemoccult scores
				0	Nothing	Normally	Normally
1	1 to 7	Semisolid	Guaiac+
				2	8 to 15	Loose stool	Bleeding+
3	＞ 15	Diarrhea	Bleeding ++

The scoring of the general form damage of table E16. colons

Score	General form
		0	Normally
1	Erythema
		2	Erythema, slight oedema, small erosion
3	Place's hemorrhagic ulcer, inflammation, moderate adhesion at two or more
		4	Severe ulcer expands narrow (stenosis with dilations), severe adhesion

The 7th day disease activity index score of table E17. and parameters score, the 9th day colon weight and length ratio and Colon Macroscopic score.

Embodiment 7

Analyzed in vitro and surface plasma resonance (SPR) analysis

Analyzed in vitro and SPR are carried out to further characterize exemplary compounds, compound C：

Ac- rings-[[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-W- [α-MeLys]-ENG-NH₂Compound C

Carry out front embodiment described in analysis with prove compound C be the effective, selective of IL-23R and Emulative inhibitor is shown to being reconciled outside people in the IL-23 dependences of phosphorylation-STAT3 (pSTAT3) in people's DB cells Effective inhibition that IFN γ generates in all blood natural kill (PB NK) cells.In addition, compound C is selective, acellular Few inhibition of the display to human Interleukin-6 R in ELISA (cell free ELISA), or the IL-12 of IFNg in PBMC are relied on Property generate in show few inhibit.Data are shown in following table E18A.Compound C also with macaque IL-23R (IC50 7nM) With rat IL-23R (IC50 17nM) cross reaction, and the IL-17A of IL-23 dependences in rat spleen cells is inhibited to generate (IC50 130nM) (data are not shown).

The vitro characterization of table E18A. compounds C

After applying (PO) to Oral Administration in Rats with 20mg/kg, the exposure of compound C is also limited to GI, for mucous membrane of small intestine, AUC Value is 355ug.h/g；For mucous membrane of colon, AUC value 77ug.h/g；And for blood plasma, AUC value 0.3ug.h/mL, The rate of recovery in middle excreta is 40%.

Compound C is also stable in various GI fluids and reducing environment, has 24 hours SIF half-life period of ＞；＞ 24 hours SGF half-life period；24 hours people's intestinal juice half-life period of ＞, and 2 hours half-life period of ＞ in DTT analyses.

Using equipped with Biacore CM4 and Xantec HC1500m sensor chips 2000 instruments of Biacore and T100 optical biosensors carry out SPR experiments.By the human IL-2 3R_huFC (RnD) of the recombination or people IL-12R β 1_ of recombination The mixture of huFC (RnD) or two kinds of receptor subunits captures on anti-human igg surface.The human IL-2 3 (Humanzyme) of recombination Or compound C is used as analyte.SPR sensorgram is fitted to one-to-one interaction model, generates the combination speed of compound Rate constant (k_on), dissociation rate constant (k_off) and dissociation constant (K_D) rough estimate, as shown in table E11.Data are shown, are changed Object C is closed not to be combined with IL-12R β 1, and respectively with the similar effect of 2.42nM and 2.56nM and IL-23R and IL-12R β 1 and The blending surface of IL-23R combines.Affinity to IL-23R and the affinity from IL-23 are comparable.In contrast, IL- 23 with secured than the affinity from the compound C about 14x of the affinity of blending surface.

Table E18B. is such as by the SPR IL-23 measured and compound C to IL-12R β 1, IL-23R or mixed IL-12R β 1 With the binding characteristic of IL-23.

Embodiment 8

The effect of IL-23R antagonists in the rat colonitis that TNBS is induced

In order to further evaluate the effect of IL-23R antagonists in animal disease model, pass through following induction acute colonic It is scorching：At the 0th day, provides straight enteral administration to the female Sprague-Dawley rats of 7 week old and contain 60mg/kg2,4,6- trinitro-s The 45%-50% ethyl alcohol (TNBS/ ethyl alcohol) of benzene sulfonic acid (TNBS).Compound C (being described in embodiment 7) with 20mg/kg or 6.7mg/kg oral administrations three times a day, and be provided in drinking water with 0.6mg/mL or 0.2mg/mL respectively, in TNBS Start within (the -1st day) about 24 hours before inoculation, continues 8 days.Anti-il-23 p 19 antibodies agent of making comparisons is neutralized, and the -1st It is with the 3rd day to be applied in 4mg/kg peritonaeums.All animals receive PBS (pH 7.4) matchmaker for being used for preparing compound C by oral administration Jie's object.Research and design is shown in Fig. 5.

In order to assess the degree of inflammatory response, the daily clinical sign for observing animal comprising weight loss percentage and The sign of loose stool or diarrhea.Six days after TNBS inoculations, rat is put to death, and it is whole to rectum to record the slave caecum of every animal A colon lengths and colon weight.By the severity for evaluating the unwitting virologist for the treatment of characteristic colitis.Except finishing Except intestinal wall thickness, the 0-4 grades according to hereafter table E19 score to Traumatic Colon substantially, and based on hereafter Parameter (table E20 and table E21) determine histopathological scores.

Table E19：The definition of colon Macroscopic score

Score	The general form of colon
		0	Normally
1	Erythema
		2	Erythema, slight oedema, small erosion
3	Place's hemorrhagic ulcer, inflammation, moderate adhesion at two or more
		4	Severe ulcer expands narrow, severe adhesion

Table E20：The definition of histopathology

Table E21：Standards of grading

Score	Mucosal necrosis
		0	Without necrosis
0.5	Very small and local region influences total colon portion of ＜ 2%
		1	Minimum lesion at most focal area influences total colon portion of 2-10%
2	Slight lesion at most focal area influences total colon portion of 11-25%
		3	The lesion of moderate at most focal area influences total colon portion of 26-50%
4	Apparent lesion at most focal area, influences total colon portion of 51-75%
		5	Serious lesion at most focal area influences total colon portion of ＞ 75%

Score	Body of gland is lost
		0	It is lossless, normal crypts epithelium and mucous membrane
0.5	Very small loss, impacted mucous membrane/body of gland are no more than 1-2 region
		1	Minimum, mucous membrane/body of gland region of 1-10% is impacted
2	Slightly, the mucous membrane of 11-25%/body of gland region is impacted
		3	Mucous membrane/body of gland region of moderate, 26-50% is impacted
4	Obviously, the mucous membrane of 51-75%/body of gland region is impacted
		5	Seriously, the mucous membrane of ＞ 75%/body of gland region is impacted

Score	Colon thickness
		0	Normally=350 microns of ＜ or thinner
0.5	Very small=351-400 microns
		1	Minimum=400-500 microns
2	Slightly=501-600 microns
		3	Moderate=601-700 microns
4	Obviously=701-800 microns
		5	Seriously=801 microns of ＞

Compared with sham-operation group, weight loss drastically is undergone with the rat of TNBS excitations, shows increased loose stool hair Raw rate and increased colon weight and length ratio.These data are confirmed by the macro -graph of colon, and there is disclosed slight Traumatic Colon, characterized by erythema, oedema and small erosion.Compared with TNBS colitis groups, weakened with the processing that compound C is carried out These variations.At high doses, compound C is significantly effectively reduced colon weight and length ratio, reduces the thickness of colon wall, And more importantly, improve the macropathology score of colon in 70% animal to normal.It (is use up except colon wall thickness Pipe trend is apparent) except all above-mentioned instructions in, observe significance,statistical under low dosage.With delivering by oral administration The mitigation of the inflammation observed of compound C (scheme with from the effect neutralized observed by anti-IL-23 p 19 monoclonal antibody is similar 6)。

The Microscopic examination showed of the lower distal colon of H＆E dyeing, the most of damage observed from medium group is transmural , it is characterized in that pass across the whole thickness of colon inflammatory cell necrosis, surface of internal cavity exist necrosis tissue debris, with And the not no crypts of mucous membrane.The part damage in mucous membrane and submucosa region is confined to the animal usually display of compound C processing Wound, colonic tissue show potential healing sign in downright bad position.Specifically, moving with the compound C processing of 160mg/kg/d Object shows that inflammation, mucosal necrosis and colon wall thickness substantially reduce, the significant decrease for causing total tissue to learn point, and from resisting Suitable (Fig. 7) that IL-23p19 antibody controls obtain.

The concentration analysis of 1 hour sample collected is shown after last PO dosage, the compound C detected from all animals Plasma concentration be less than compound IC75 ＜=2X, the IC75 is as based on rat spleen cells/IL-17A cells Measured in analysis or in rat IL-23R ELISA, show from be orally administered the effect of observing most-likely due to its Topically active in colon (referring to Fig. 8).Generally speaking, these data highlight IL-23R antagonists in TNBS colitis Developing protective effect.

These studies have shown that the present invention peptide be effective, selective and orally active IL-23R peptide antagonists, It is the promising therapeutic agent for treating IBD and other illnesss.As shown here, the present invention provides such peptide：It is behaved The effective blocking agent of IL-23/IL-23R signal transductions in cell line and people's primary cell；It is selective to IL-23R, and Do not inhibit and the combination of IL-6R or does not inhibit signal transduction by IL-12R；For rat homologues and macaque homologue It is cross reaction, but for mouse homolog no cross reaction, makes it possible the In vivo study in these species；It is right The proteolysis and reducing environment of GI has repellence, causes the limited drug in the high levels of drugs and cycle in intestinal tissue dense Degree provides potential security advantages compared with the therapeutic agent of systemic delivery；And in the rat colonitis mould for weakening TNBS inductions It is effective and suitable with anti-IL23p19 monoclonal antibodies in terms of colitis in type, the activity aspect being limited by GI- is most It is similar.

Embodiment 9

The vitro characterization of exemplary IL-23R antagonists

In order to evaluate effect property, SEQ ID NO are carried out as described above：980 (peptides 980), 993 (peptides 993) and 1185 (peptides 1185) IL-23R peptide antagonists are tested to determine the effect, selectivity and stability of peptide.Such as by competing to IL-23/IL-23R Peptide measured by the quantitative ELISA (carrying out as described in Example 2) of striving property binding analysis is for people (Hu), machin (Cyno) and the IL-23 and IL-23R of rat (Rat) combine IC₅₀Value is shown in table E22.As described above, also passing through IL-23R The effect of peptide is evaluated in activity analysis.Pass through phosphorylation-STAT3 (pSTAT3) water in the people's DB cells for being exposed to IL-23 Flat reduction (Hu DB cells (pSTAT3)；It carries out as described in Example 2)；It is thin by the people NK by being exposed to IL-23 Reduction (the Hu NK cells of IFN γ caused by born of the same parents；It carries out as described in Example 5)；And by by being exposed to IL- Reduction (the rat (spleen) of IL-17A caused by 23 activated splenocytes；Carry out as described in Example 6) it determines The IC of peptide₅₀Value.Inhibit 1 interactions (referring to embodiment 4) of human IL-2 3/IL-12R β or people IL-6/IL-6R mutual by measurement Act on the IC of the peptide of (referring to embodiment 6)₅₀To evaluate selectivity.It is exposed to simulated intestinal fluid (SIF), simulate the gastric juice by measuring (SGF) or half-life period of the peptide of people's intestinal juice (SIF) determines the stability of peptide.

The property of the exemplary IL-23R antagonist peptides of table E22.

The structure of peptide 993 is as follows：

Ac- [(D)-Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino- 4- carboxyls-oxinane]-ENN-NH₂(SEQ ID NO：993)

The structure of peptide 1185 is as follows：

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- carboxyls-four Hydrogen pyrans]-[Lys (Ac)]-NN-NH₂(SEQ ID NO：1185)

The structure of peptide 980 is as follows：

Ac- rings-[[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]]-[2-Nal]-[4- amino -4- carboxyls-four Hydrogen pyrans]-ENN-NH₂(SEQ ID NO：980)

It is being summarized in table E22 the result shows that compared with IL-23/IL-12R β 1 or IL-6/IL-6R interact, the peptide Effectively and selectively IL-23/IL-23R is inhibited to combine.It is produced with IL-23R- dependences such as STAT3 phosphorylations, IFN γ is measured Give birth to confirms this inhibition with the cell culture assays of IL-17A generations.Also determine that the peptide is being exposed to simulated intestinal fluid, simulation There is high stability when gastric juice or mankind's intestinal juice.

The data tested from people DB cells (pSTAT3) analyze (referring to Figure 17) for Schild.For Schild points Analysis, tests the peptide 993 of a concentration of 0.3nM, 1nM, 3nM, 10nM, 30nM, 100nM.Schild slopes are determined as 1.068, table Bright peptide 993 shows as simple competitive antagonist.Also to SEQ ID NO：The peptide of 1169 structures has carried out Schild points Analysis, the peptide are similar with the structure height of peptide 1185.Schild slopes are determined as 0.91, show peptide with similar structure (packet Include peptide 1185) simple competitive antagonist may be shown as.Also to SEQ ID NO：1211 peptide has carried out Schild analyses, The peptide has the structure similar with peptide 980.Sehild slopes are determined as 0.76.But when slope is fixed as 1, R²Value is 0.975.These are statistics indicate that peptide with similar structure (including peptide 1185) can show as simple competitive antagonist.

Embodiment 10

The internal pharmacokinetics of exemplary IL-23R antagonists

The pharmacokinetic property of exemplary peptides is measured in vivo.To Sprague Dawley rats using 10mg/kg's Peptide 993 (P.O.).

Be with or without arbitrarily supply drinking water dosage in the case of, it is (every to normal female Sprague-Dawley rats N=3 rat of a time point) using the peptide 933 of single oral dose (referring to Figure 11).After oral dose, upon administration 0.25, determining exposure of the peptide 993 in blood plasma in 0.5,1,3,6,8 and 24 hour.It is 1,3,6,8 and 24 hour upon administration, also true Peptide 993 is determined in small intestine, colon, mucous membrane of small intestine, mucous membrane of colon, intestinal mucus, peyer's patches and lymphonodi mesenterici (MLN) It is horizontal.Urine and excreta were collected at 6 and 24 hours to determine the excretion of peptide 993.Blood plasma, excreta and tissue sample are being analyzed It is stored in -80 ± 10 DEG C before.For blood plasma, is used using 50 μ L samples and solution (MeOH: ACN is quenched with internal standard W/0.1% formic acid, 50: 50 volumes) compound extracted by albumen precipitation.For excreta, before extraction by sample with 0.1% aqueous formic acid (water: the ratio of excreta is 4: 1) homogenate.It is homogenized using 50 μ L excretas, using with internal standard The solution (MeOH: ACN w/0.1% formic acid, 50: 50 volumes) that is quenched compound is extracted by albumen precipitation.For such as tying The tissue of intestines or small intestine, by sample and 0.1% aqueous formic acid (water: the ratio of tissue is 3: 1) homogenate before extraction.For The tissue of such as peyer's patches and lymphonodi mesenterici, by sample and 0.1% aqueous formic acid (water: tissue before extraction Ratio is 20: 1) being homogenized.It is homogenized using the tissue of 50 μ L, solution (MeOH: ACN w/ is quenched using with internal standard 0.1% formic acid, 50: 50 volumes) compound extracted by albumen precipitation.The albumen of precipitation is removed by filter plate, and will be received The supernatant of collection is dry and redissolves.The sample of processing is analyzed on 4000 mass spectrographs of AB/MDS Sciex API.In more reaction prisons Cation is monitored under (MRM) pattern of survey.It is quantified by peak area ratio.

0-24 hours after application, the peptide 993 of detectable level is not observed in rat plasma (referring to Figure 11 A). In contrast, in peyer's patches and small intestine there is at least 6 hours (referring to Figure 11 B and Figure 11 C) in the peptide 993 of detectable level, And there is at least 8 hours (referring to Figure 11 D) after colon administration.It 24 hours after application, is detected in rat excreta More than 5% level of total administration dosage of peptide 993, further demonstrate that peptide 993 has high oral stability.In short, these As a result it proves that peptide 993 is to take orally stable GI restricted peptides, shows high GI contents and limited whole body after oral administration Distribution.

The peptide 1185 (P.O.) of 10mg/kg is applied to Sprague Dawley rats.To normal female Sprague- The peptide 1185 of the single oral dose of Dawley rats (N=3 rat of each time point) application.After oral dose, to Until measuring exposure of the peptide 1185 in blood plasma in 8 hours samples taken after medicine.The urine and excreta of collection a few hours is with true Determine the excretion (Figure 18) of peptide 1185.

The peptide 980 (P.O) of 10mg/kg is applied to Sprague Dawley rats.To normal female Sprague-Dawley The peptide 980 of the single oral dose of rat (N=3 rat of each time point) application.After oral dose, upon administration until Exposure of the peptide 980 in blood plasma is measured in 8 hours samples taken.The urine and excreta of collection a few hours is to determine peptide 980 Excretion (Figure 19).

Embodiment 11

The safety overview of exemplary IL-23R antagonists

The safety overview of exemplary peptides inhibitor is characterized.In the safety of inspection and the combination of 44 target groups Peptide 993 and peptide 1185 are evaluated in group.Target includes g protein coupled receptor (GPCR), transport protein (such as dopamine transporter And ion channel (DAT)).For all targets, these peptides show it is inactive, such as by more than the active change of 25% target Defined in changing and (inhibiting or stimulate).Table E24 lists the target tested in security group.For each target, up to Determine that peptide 993 and peptide 1185 are inactive under 10 μM of concentration.By evaluating peptide 980 selected from the test compound of table E24 Safety overview.For all tested compounds, peptide 980 only shows medium activity in acetylcholinesteraseanalysis analysis (33%), any activity and is not shown in other aspects, as by more than defined in the active variation of 25% target.

Table E24. peptides 993 and peptide 1185 are inactive in security group

Embodiment 12

Effect of the exemplary peptides inhibitor in the rat model of acute colitis

In order to evaluate the effect of exemplary peptides inhibitor peptide 1185 in animal disease model, by the 0th day to 7 week old Female Sprague-Dawley rats provide the 64mg/kg TNBS that are applied in 50% ethyl alcohol in rectum to induce acute colonic It is scorching.37mg/kg/ days peptides 1185 (combining PO and in drinking water), PO BID were administered orally at the -1st day to the 7th day.It will not The TNBS treatment groups for being exposed to the sham-operation group of TNBS and receiving medium processing are used as control group.For comparing agent, - Anti-il-23 p 19 antibodies were neutralized to be applied in 4mg/kg peritonaeums within 1 day, and the interior application of peritonaeum again on day 3, and with 10mg/ days P.O. prednisolone is applied.The oral water received as the medium for preparing peptide 993 of all animals.

As described above, observing the clinical sign of animal daily comprising the sign of weight loss percentage and loose stool or diarrhea As.6 days after being inoculated with TNBS, rat is put to death, and record the entire colon lengths and colon weight of every animal.By virologist Evaluate the severity of colitis.Other than colon wall thickness, it is 0-5 etc. that Traumatic Colon substantially, which is scored, according to table E29 Grade, and histopathological scores are determined based on the parameter listed in table E30.

Some diseases what is observed in the TNBS rat models of acute colitis are significantly reduced with the processing of peptide 1185 Sick parameter.When continued weight increases the rat in sham-operation group in entire research process, it is exposed to TNBS and uses medium The rat of processing undergoes weight loss.It is exposed to prednisolone oral medication or with the prevention of anti-IL-23p19 systemic therapies The weight loss of the rat of TNBS.The treatment that peptide 1185 is administered orally subtracts without significantly preventing the weight of the rat of TNBS excitations Gently (referring to Figure 13).Compared with being handled with medium, after with prednisolone or anti-IL-23 p 19 processing, colon weight is also observed The ratio between amount and colon lengths significantly reduce.Peptide 1185, which is administered orally, leads to colon weight and colon in the rat for being exposed to TNBS Length ratio reduction similar with colon Macroscopic score.Higher colon Macroscopic score shows the colon pathology of higher degree. It is (all these to pass through for adhesion, narrow, ulcer and colon wall thickness by addition compared with the control of medium processing Handled and significantly reduced with prednisolone, anti-IL-23 p 19 or peptide 1185) scoring determine colon Macroscopic score.These data Show that peptide 1185, which is administered orally, has effect suitable with systemic administration anti-IL-23 p 19 monoclonal antibody.

Check be derived from sham-operation group, medium group, 1185 groups of anti-IL-23 p 19 and peptide rat colon histotomy Pathological characteristics.According to the standard listed in table E29, mucosal inflammation, transmural inflammation, body of gland loss and erosion are commented Point.For all these features, is reduced with the processing of anti-IL-23 p 19 or prednisolone and expose related tissue disease with TNBS Neo-Confucianism scoring.Histopathological scores are not significantly reduced with the treatment of peptide 1185.

Embodiment 13

Effect of the exemplary peptides inhibitor in the rat model of acute colitis

In order to evaluate the effect of exemplary IL-23R inhibitor peptides peptide 993 in animal disease model, by the 0th day to It is acute to induce that 7 week old female Sprague-Dawley rats provide the 64mg/kg TNBS being applied in 50% ethyl alcohol in rectum Colitis.The beginning in (the -1st day) about 24 hours before TNBS inoculations, is administered orally 2 times with 10mg/kg, in total daily by peptide 993 42mg/kg/ days, continue 8 days.By the sham-operation group for being not exposed to TNBS and receive medium processing TNBS treatment groups be used as pair According to group.The oral water received as the medium for preparing peptide 993 of all animals.

All diseases what is observed in the TNBS rat models of acute colitis are significantly reduced with the treatment of peptide 993 Parameter.When continued weight increases the rat in sham-operation group in entire research process, it is exposed to TNBS and at medium The rat of reason undergoes weight loss.Be administered orally peptide 993 treatment also prevent TNBS excitation rat weight loss (referring to Figure 12).In addition, after 993 peptides are administered orally and are treated, also observe that the ratio between colon weight and colon lengths significantly reduce. Higher colon Macroscopic score shows the colon pathology of higher degree, and compared with the control of medium processing, passes through use Peptide 993 is treated, and colon Macroscopic score significantly reduces.Peptide 993 is administered orally with anti-with systemic administration anti-IL-23 p 19 monoclonal The suitable effect of body (being used as positive control).Compared with medium group, in the colon for the rat treated from peptide 993, tissue Histological scores significantly reduce.

Embodiment 14

Effect of the exemplary peptides inhibitor in the rat model of acute colitis

In order to evaluate the effect of exemplary IL-23R inhibitor peptides peptide 980 in animal disease model, by the 0th day to It is acute to induce it to be applied in the 64mg/kgTNBS in 50% ethyl alcohol in 7 week old female Sprague-Dawley rats offer rectum Colitis.37mg/kg/ days peptides 980 (combining PO and in drinking water), PO BID were administered orally at the -1st day to the 7th day.It will The TNBS treatment groups for being not exposed to the sham-operation group of TNBS and receiving medium processing are used as control group.All animals are oral to be connect By the PBS as the medium for preparing peptide 980.

As described above, observing the clinical sign of animal daily comprising the sign of weight loss percentage and loose stool or diarrhea As.6 days after being inoculated with TNBS, rat is put to death, and record the entire colon lengths and colon weight of every animal.By virologist Evaluate the severity of colitis.Other than colon wall thickness, it is 0-5 etc. that Traumatic Colon substantially, which is scored, according to table E29 Grade, and histopathological scores are determined based on the parameter listed in table E30.It is significantly reduced acute with the treatment of peptide 980 All disease parameters what is observed in the TNBS rat models of colitis.

The weight loss of the rat of the Prevention TNBS excitations of peptide 980 is administered orally (referring to Figure 14).In addition, oral After administrated peptide 980 is treated, the significant decrease of the ratio between colon weight and colon lengths is also observed.Higher colon macroscopic view is commented Divide the colon pathology for showing higher degree, and compared with the control of medium processing, by being treated with peptide 980, colon is macro Seeing scoring significantly reduces (referring to Figure 14).

Check the pathology of the histotomy of the colon for the rat for being derived from 980 treatment group of sham-operation group, medium group and peptide Feature.According to the standard listed in table E30, scored mucosal inflammation, transmural inflammation, body of gland loss and erosion (referring to figure 14D).Compared with medium, the treatment of peptide 980 significantly reduces the summation of histopathological scores.

Embodiment 15

In the rat model of acute colitis after being treated with inhibitor peptides biomarker level

The level of Inflammatory Mediators is detected in colon.The lower distal colon tissue sample for protein expression analysis will be specified It is rapidly frozen after collection.For protein extraction, sample is thawed, weigh and (is supplemented with protease to inhibit in Extraction buffer The PBS of agent, pH 7.2,3 × volume：Weight) in homogenate.Homogenate is centrifuged 15 minutes at 4 DEG C with 13krpm, in total twice to remove Remove fragment.Supernatant is stored in -80 DEG C in multiple aliquots, the protein expression analysis being used subsequently on ELISA.It uses BCA analyses quantify the total protein in each sample.Lower distal colon is analyzed using commercially available rat ELISA kit The expression of MPO, IL-1 β, IL-6, IL-17A and IL-22 albumen in sample.

The treatment of peptide 993 reduces the level of Inflammatory Mediators present in colon.Compared with the control of medium processing, Reduce the disease defined by (MPO, IL-6 and IL-1 β) with the treatment of peptide 993 and for the biomarker (IL- of IL-23 22 and IL-17A) (referring to Figure 15).These statistics indicate that, the amount administrated peptide 993 can reduce internal pathology also reduces knot Present in intestines with the level of the relevant biomarker of IL-23R activity.Compared with the control of medium processing, with peptide 980 Treatment reduces the level of MPO and IL-22 (referring to Figure 16).It is not significantly reduced with the treatment of peptide 1185 under proof load The level of MPO, IL-22 or IL-17A.

Table E29. colon Macroscopic scores

Table E30a. histopathologies-mucous membrane/submucosal inflammation scoring

Table E30b

Table E30c

Table E30d

Table E30e

Table E30f

Histopathology summation
	Calculate inflammation, the summation of body of gland loss, rotten to the corn and transmural inflammation scoring.

Embodiment 16

Other peptide inhibits the characterization that Interleukin-23 is combined with Interleukin-23 receptor

The optimization of peptide is carried out to identify active under low concentration (for example, IC50 ＜ 10nM) while stomach and intestine (GI) are presented The other inhibitor peptides of the IL-23 signal transductions of stability.As described below, certain peptides are tested and inhibits IL- to identify 23 are combined with human IL-2 3R and are inhibited the peptide of IL-23/IL-23R functional activities.The peptide tested includes containing various different cyclisation The peptide of chemical substance comprising the peptide containing disulfide bond and the peptide containing thioether bond for example between two Pen residues.This hair Bright inhibitor peptides include but not limited to the peptide with any structure described herein.In addition, the inhibitor peptides packet of the present invention It includes with those of identical as the amino acid sequence of peptide as described herein or structure, without with identical or any N-terminal or C Hold " sealing end " group, such as Ac or NH₂。

As described in Example 2, carried out analysis is carried out to determine peptide activity.People ELISA indicates IL23- IL23R competitive binding analysis, rat ELISA indicate the analysis of rat IL-23R competitive binding ELISAs and pStat3HTRF Indicate DB cell IL-23RpSTAT3 cell analysis.Peptide described in table E31 between two residues in these peptides via forming Disulphide bridges and be cyclized.Peptide described in table E32 is cyclized via the thioether bond between shown amino acid residue.Table E32, which is provided, to be retouched The example arrangement of thio-ether cyclization is stated, can also be indicated by term " ring " in table, followed by the ring region for adding square brackets.

Table E31. contains the exemplary peptides of Ac- [Pen]-XXWX- [Pen]-XXXX motifs and analog

The IC50 of table E32. exemplary peptides inhibitor (thioether)

Ac- rings-[[Abu]-XXWXC]-[Phe (4-OMe)]-[2-Nal]-XXX-NH₂

* ＜ 10nM；* >=10 and ＜ 100nM；* >=100 * and≤1,000nM

Embodiment 17

The stability of simulated intestinal fluid (SIF), simulate the gastric juice (SGF) and the other inhibitor peptides under Redox Condition

It is studied in simulated intestinal fluid (SIF) and simulate the gastric juice (SGF) to evaluate the other inhibitor peptides of the present invention Stomach stability.In addition, being studied the oxidation-reduction stability of the other inhibitor peptides to assess the present invention.

Table E33. thioethers and Dipens

＞ 90=are less than or equal to 180 minutes and are more than 90 minutes；＞ 45min=are less than or equal to 90 minutes and are more than 45 Minute；＞ 10=are less than or equal to 45 minutes and are more than 10 minutes；＜ 10=are less than 10 minutes.

Embodiment 18

NK cell analysis

It will be by Solid phase (Miltenyi Biotech, catalogue #130-092-657) from the human peripheral of healthy donors Natural kill (NK) cell of purifying, (contains 10%FBS, L-Glutamine and Pen .- Strep in complete medium RPMI 1640) it is cultivated there are the IL-2 of 25ng/mL (RnD catalogue #202-IL-010/CF).After 7 days, Cell is centrifuged, and is resuspended in complete medium with 1E6 cell/mL.By the recombinant il-2 3 of scheduled EC50 to EC75 with And the IL-18 (RnD, catalogue #B003-5) of 10ng/mL is mixed with the peptide of various concentration, and be added to and connect with 1E5 cells/well In the NK cells of kind.After 20-24 hours, quantified in supernatant using Quantikine ELISA (RnD, catalogue #DIF50) IFNγ.As a result it is shown in table E34.It is multiple the result is that from individually analysis shown in single peptide.

Table E34. primary cells analyze (thioether and Dipens)

All above-mentioned United States Patent (USP)s, the United States Patent (USP) that will in the present specification refer to and/or listed in application data form Application publication object, U.S. Patent application, foreign patent, foreign patent application and non-patent publications are integrally incorporated this by reference Text.

Although from the foregoing it will be appreciated that there is described herein specific embodiments of the present invention for illustrative purposes, It is that various modifications can be carried out without departing from the spirit and scope of the present invention.Therefore, the present invention is not by addition to appended Limitation except claim.

Claims

1. the inhibitor peptides of Interleukin-23 receptor or its pharmaceutically acceptable salt or solvate, wherein the peptide presses down Preparation includes the amino acid sequence of formula (Xa)：

X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (Xa)

Wherein

X1 is arbitrary amino acid or is not present；

X2 is arbitrary amino acid or is not present；

X3 is arbitrary amino acid or is not present；

X5 is arbitrary amino acid；

X6 is arbitrary amino acid；

X7 is arbitrary amino acid；

X8 is arbitrary amino acid；

X10 is arbitrary amino acid；

X11 is arbitrary amino acid；

X12 is arbitrary amino acid；

X13 is arbitrary amino acid；

X14 is arbitrary amino acid；

X15 is arbitrary amino acid,

X16 is arbitrary amino acid or is not present；

X17 is arbitrary amino acid or is not present；

X18 is arbitrary amino acid or is not present；

X19 is arbitrary amino acid or is not present；And

X20 is arbitrary amino acid or is not present,

2. the key between inhibitor peptides as described in claim 1, wherein X4 and X9 is disulfide bond, thioether bond, lactam bond, three Azoles ring, selenide key, two selenium keys or alkene key.

3. inhibitor peptides as described in claim 1, wherein X4 are Cys, X9 Cys, and the key is disulfide bond.

4. inhibitor peptides as described in claim 1, wherein X4 are Pen, X9 Pen, and the key is disulfide bond.

5. inhibitor peptides as described in claim 1, wherein the inhibitor peptides include SEQ ID NO：365-370、857- Any of 1029 amino acid sequence.

6. inhibitor peptides as described in claim 1, wherein the inhibitor peptides include formula (Va), (Vb), (Vc), (Vd), (Ve), amino acid sequence shown in any of (Vf), (Vg) and (Vh).

7. inhibitor peptides as described in claim 1, wherein the inhibitor peptides include any of following amino acid sequences：

[Palm]-[different Glu]-[PEG4]-[Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]- [Aib]-[Lys(Ac)]-NNNH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (different Glu- of PEG4- Palm)]-NN-NH₂；

Ac-[Pen]-QTWQ-[Pen]-Phe(4-CONH₂)-[2-Nal]-[α-MeLys(Ac)]-[Lys(Ac)]-NN-NH₂；

[octyl]-[different Glu]-[PEG4]-[Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]- [Aib]-[Lys(Ac)]-NN-NH₂；

[octyl]-[PEG4]-[Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂；

[Palm]-[PEG4]-[Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)-(PEG4-Palm)]-[2-Nal]-[Aib]-[Lys (Ac)]NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)-(PEG4- lauryls)]-[2-Nal]-[Aib]- [Lys(Ac)]-NN-NH₂；

Ac-[Pen]-QTWQ-[Pen]-Phe(4-CONH₂)-[2-Nal]-[α-MeLys(PEG4-Palm)-[Lys(Ac)]-NN- NH₂；

Ac-[Pen]-QTWQ-[Pen]-Phe(4-CONH₂)-[2-Nal]-[α-MeLys (PEG4- lauryls)]-[Lys (Ac)]- NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)-(the different Glu- lauryls of PEG4-)]-[2-Nal]- [Aib]-[Lys(Ac)]-NN-NH₂；

Ac-[Pen]-QTWQ-[Pen]-Phe(4-CONH₂)-[2-Nal]-[α-MeLys (the different Glu-Palm of PEG4-)]-[Lys (Ac)]-NN-NH₂；

Ac-[Pen]-QTWQ-[Pen]-Phe(4-CONH₂)-[2-Nal]-[α-MeLys (the different Glu- lauryls of PEG4-)]-[Lys (Ac)]-NN-NH₂；

Ac-[Pen]-QTWQ-[Pen]-Phe(4-CONH₂)-[2-Nal]-[α-MeLys(IVA)]-[Lys(Ac)]-NN-NH₂；

Ac-[Pen]-QTWQ-[Pen]-Phe(4-CONH₂)-[2-Nal]-[α-MeLys (biotin)]-[Lys (Ac)]-NN- NH₂；

Ac-[Pen]-QTWQ-[Pen]-Phe(4-CONH₂)-[2-Nal]-[α-MeLys (octyl)]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-[Lys (IVA)]-TWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (IVA)]-N-NH₂；

Ac- [Pen]-[Lys (biotin)]-TWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]- [Lys(Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (biotin)]-N-NH₂；

Ac- [Pen]-[Lys (octyl)]-TWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (octyl)]-N-NH₂；

Ac- [Pen]-[Lys (Palm)]-TWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal] -- [Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-Lys (Palm)]-N-NH₂；

Ac- [Pen]-[Lys (PEG8)]-TWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (PEG8)]-N-NH₂；

Ac- [Pen]-K (Peg11-Palm) TWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal] -- [Aib]-[Lys (Ac)]-[Lys (Peg11-palm)]-N-NH₂；

Ac- [Pen]-[Cit]-TW- [Cit]-[Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal] -- [Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-[Lys (Ac)]-TW- [Cit]-[Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]- [Lys(Ac)]-NN-NH₂；

Ac- [Pen]-NT- [Phe (2,4-CH3) 2]-Q- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]- [Lys(Ac)]-NN-NH₂；

Ac- [Pen]-NT- [Phe (3-CH3)]-Q- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]- [Lys(Ac)]-NN-NH₂；

Ac- [Pen]-NT- [Phe (4-CH3)]-Q- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]- [Lys(Ac)]-NN-NH₂；

Ac- [(D) Tyr]-[Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-N-[βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-QN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (Ac)]-N-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-N- [Lys (Ac)]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-QQ-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-Q- [β Ala]-NH2；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Cit]- NNH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Cit]- Q-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Cit]- [Lys(Ac)]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Lys (Ac)]-[Cit]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-QN- [β Ala]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-E- [Cit]-Q-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Cit]-N- [Cit]- NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Cit]-Q- [Cit]- NH₂；

Ac- [Pen]-[Cit]-TWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-QNN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-ENQ-NH₂；

Ac- [Pen]-GPWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-PGWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NTWN- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NSWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-N- [Aib]-WQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- NN-NH₂；

Ac- [Pen]-NTW- [Aib]-[Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)] N- [Aib]-NH₂；

Ac- [Pen]-QTW- [Lys (Ac)]-[Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-[Lys (Ac)]-TWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal] -- [Aib]-[Lys (Ac)]NNNH₂；

Ac- [Pen]-QVWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[α-MeLeu]-[Lys (Ac)]- NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[α-MeLys]-[Lys (Ac)]- NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- carboxyls-tetrahydrochysene pyrrole Mutter]-[Lys (Ac)]-NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[α-MeLeu]-[Lys (Ac)]-N- [βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[α-MeLys]-[Lys (Ac)]-N- [βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- carboxyls-tetrahydrochysene pyrrole Mutter]-[Lys (Ac)]-N- [β Ala]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-LN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-GN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-SN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Aib]- N-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-FN-NH₂；

Ac- [Pen]-NTW- [Cit]-[Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]- NN-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-[Tic]- [βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-G- [β Ala]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-R- [β Ala]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal] -- [Aib]-[Lys (Ac)]-W- [β Ala]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal] -- [Aib]-[Lys (Ac)]-S- [β Ala]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal] -- [Aib]-[Lys (Ac)]-L- [β Ala]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal] -- [Aib]-[Lys (Ac)]-[N- MeAla]-[βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-[2- Nap]-[βAla]-NH₂；

Ac- [Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[Aib]-[Lys (Ac)]-F- [β Ala]-NH₂；

Ac- [(D) Arg]-[Pen]-NTWQ- [Pen]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- carboxylics Base-oxinane]-[Lys (Ac)] NNNH₂；

Biotin-[PEG4]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- carboxylics Base-oxinane]-ENN-NH₂；

Ac- rings [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- carboxyls-tetrahydrochysene pyrrole Mutter]-[Lys (Ac)]-NN-NH₂；

Ac- [(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- carboxylics Base-oxinane]-[Lys (Ac)]-NN-NH₂；

Ac-E- [(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- carboxylics Base-oxinane]-ENN-NH₂；

Ac- [(D) Asp]-[(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- ammonia Base -4- carboxyls-oxinane]-ENN-NH₂；

Ac-R- [(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- carboxylics Base-oxinane]-ENN-NH₂；

Inoethoxy)]-[2-Nal]-[4- amino -4- carboxyls-oxinane]-ENN-NH₂；

Ac-F- [(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- carboxylics Base-oxinane]-ENN-NH₂；

Ac- [(D) Phe]-[(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- ammonia Base -4- carboxyls-oxinane]-ENN-NH₂；

Ac- [2-Nal]-[(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- ammonia Base -4- carboxyls-oxinane]-ENN-NH₂；

Ac-T- [(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- carboxylics Base-oxinane]-ENN-NH₂；

Ac-L- [(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino -4- carboxylics Base-oxinane]-ENN-NH₂；

Ac- [(D) Gln]-[(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- ammonia Base -4- carboxyls-oxinane]-ENN-NH₂；

Ac- [(D) Asn]-[(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- ammonia Base -4- carboxyls-oxinane]-ENN-NH₂；

Ac- rings [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)-(PEG4-Alexa488)]-[2-Nal]-[4- ammonia Base -4- carboxyls-oxinane]-ENN-NH₂；

[Alexa488]-[PEG4]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)] -- [2-Nal]-[4- ammonia Base -4- carboxyls-oxinane]-ENN-NH₂；

[Alexa647]-[PEG4]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2-Nal]-[4- amino- 4- carboxyls-oxinane]-ENN-NH₂；

[Alexa-647]-[PEG4]-[(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2- Nal]-[4- amino -4- carboxyls-oxinane]-[Lys (Ac)]-NN-NH₂；

[Alexa647]-[PEG12]-[(D) Arg]-ring [[Abu]-QTWQC]-[Phe [4- (2- amino ethoxies)]-[2- Nal]-[4- amino -4- carboxyls-oxinane]-[Lys (Ac)]-NN-NH₂；And

The wherein described inhibitor peptides via between 2 Pen residues disulfide bond or pass through the thioether bond between Abu and Cys residues Cyclisation, and the wherein described inhibitor peptides inhibit the combination of Interleukin-23 (IL-23) and IL-23 receptor.

8. the inhibitor peptides as described in any one of claim 1-7, also include be conjugated to one of the inhibitor peptides or Multiple half-life extension moieties and/or one or more junction portions.

9. inhibitor peptides as claimed in claim 8, wherein the half-life extension moiety is via one or more junction portions It is conjugated to the inhibitor peptides.

10. inhibitor peptides as claimed in any one of claims 1-9 wherein or its pharmaceutically acceptable salt or solvate, wherein The inhibitor peptides include the structure of Formulas I：

R¹-X-R²(I)

Wherein

R¹For key, hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl, C1-C6 alkyl, C1-C20 hydrocarbon acyl groups, and include Any one of aforementioned individual PEGylated forms or the PEGylated forms as introns；X is amino acid sequence；With And

R²For OH or NH₂。

11. the peptide dimer inhibitor of Interleukin-23 receptor, wherein the peptide dimer inhibitor include via one or Two peptide monomer subunits of multiple junction portion connections, wherein each peptide monomer subunit has any one of claim 1-10 institutes The sequence or structure shown.

12. peptide dimer inhibitor as claimed in claim 11, wherein one or two peptide monomer subunit via X4 and X9 it Between intramolecular bond cyclisation.

13. peptide dimer inhibitor as claimed in claim 12, wherein one or two intramolecular bond is disulfide bond, thioether Key, lactam bond, selenide key, two selenium keys or alkene key.

14. the peptide dimer inhibitor as described in any one of claim 11-13, wherein the junction portion is diethylene glycol Connector, iminodiacetic acid (IDA) connector, β-Ala- iminodiacetic acids (β-Ala-IDA) connector or PEG connectors.

15. the peptide dimer inhibitor as described in any one of claim 11-14, wherein the ends N- of each peptide monomer subunit are logical The junction portion connection is crossed, or the ends C- of wherein each peptide monomer subunit are connected by the junction portion.

16. the peptide two as described in any one of inhibitor peptides or claim 11-15 as described in any one of claim 1-10 Aggressiveness also includes the chemical substituents being conjugated.

17. inhibitor peptides as claimed in claim 16 or peptide dimer, wherein the conjugated chemical substituents are lipophilicitys Substituent group or polymer moieties.

18. inhibitor peptides as claimed in claim 16 or peptide dimer, wherein the conjugated chemical substituents be Ac, Palm, γ Glu-Palm, the different Glu-Palm of different Glu-Palm, PEG2-Ac, PEG4-, (PEG)₅- Palm, succinic acid, glutaric acid, Pyroglutamic acid, benzoic acid, IVA, octanoic acid, 1,4-Diaminobutane, isobutyl group or biotin.

19. inhibitor peptides as claimed in claim 16 or peptide dimer, wherein the conjugated chemical substituents are molecular weight For the polyethylene glycol of 400Da to 40,000Da.

20. polynucleotides, it includes the inhibitor peptides or claim 11-15 described in any one of coding claim 1-10 Any one of described in peptide dimer inhibitor one or two peptide monomer subunit sequence.

21. carrier, it includes the polynucleotides described in claim 20.

22. pharmaceutical composition, it includes the inhibitor peptides or peptide dimer inhibitor described in any one of claim 1-19, with And pharmaceutically acceptable carrier, excipient or diluent.

23. pharmaceutical composition as claimed in claim 22 also includes enteric coating.

24. pharmaceutical composition as claimed in claim 23, wherein the enteric coating is protected described pharmaceutical composition and made It is released in the lower gastrointestinal tract system of object.

25. the method for following disease in treatment object：Inflammatory bowel disease (IBD), ulcerative colitis, Crohn disease, breast Gruel rush down (nontropical sprue), with the relevant enteropathy of seronegative arthropathy, microscopic colitis, Collagen Colitis, eosinophilic gastroenteritis, the elder generation with radiotherapy or the relevant colitis of chemotherapy and such as 1 type of leukocyte adhesion deficiency disease The relevant colitis of its immune disorders, chronic granulo matosis, glycogen storage disease 1b types, Hermansky-Pudlak syndromes, After Chediak-Higashi syndromes and Wiskott-Aldrich syndromes, proctocolectomy and ileoanal anastomosis Caused haustrum inflammation, human primary gastrointestinal cancers, pancreatitis, insulin-dependent diabetes mellitus, mastitis, cholecystitis, cholangitis, bile duct week Inflammation, chronic bronchitis, chronic sinusitis, asthma, psoriasis, psoriasis arthropathica or graft versus host disease(GVH disease), the method Include the inhibitor peptides or peptide dimer inhibitor provided to the object described in any one of a effective amount of claim 1-19 Or the pharmaceutical composition described in any one of claim 22-24.

26. method as claimed in claim 25, wherein passing through oral administration path, parenteral administration approach, intravenous application Approach, peritonaeum administration method, intradermal administration approach, subcutaneous administration approach, intramuscular administration method, intrathecal administration method, sucking Administration method, vaporization administration method, atomization administration method, sublingual administration route, oral administration approach, parenteral administration approach, Rectal administration approach, intraocular administration method, sucking administration method, topical routes of administration, vaginal application approach or local application way The radial object provides described pharmaceutical composition.

27. method as claimed in claim 25 is used to treat inflammatory bowel disease (IBD), ulcerative colitis, Crow grace Disease, wherein providing described pharmaceutical composition to the object by oral administration.

28. method as claimed in claim 25 is used to treat psoriasis, wherein by oral administration, part, parenteral, it is intravenous, Subcutaneously, peritonaeum or vein are interior to object offer pharmaceutical composition.

29. the method as described in any one of claim 25-28, wherein the inhibitor peptides or the peptide dimer inhibitor Inhibit the combination of Interleukin-23 (IL-23) and Interleukin-23 receptor (IL-23R).