MXPA97002666A - New peptides with immunoregulated effects - Google Patents
New peptides with immunoregulated effectsInfo
- Publication number
- MXPA97002666A MXPA97002666A MXPA/A/1997/002666A MX9702666A MXPA97002666A MX PA97002666 A MXPA97002666 A MX PA97002666A MX 9702666 A MX9702666 A MX 9702666A MX PA97002666 A MXPA97002666 A MX PA97002666A
- Authority
- MX
- Mexico
- Prior art keywords
- pro
- yespro
- yes
- xes
- phe
- Prior art date
Links
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Abstract
New peptides according to formula (I), A-X-Y-Cys-Z-B, a process for the preparation and its use in the manufacture of pharmaceutical preparations. The new peptides are excellent as immunoregular
Description
NEW PEPTIDES WITH IMMUNOREGUADORBS EFFECTS
FIELD OF THE INVENTION
The present invention relates to novel peptides, a method for the preparation of peptides and a pharmaceutical preparation containing the peptides. The peptides according to the present invention are excellent as immunoregulatory agents.
There has been a long felt need for new safe immunoregulatory agents in the treatment of many different diseases including malignant diseases, autoimmune diseases and asthma / allergy. The current immunoregulatory agents such as Cyclosporin A and steroids are very potent immunosuppressive agents but also exhibit severe side effects in a dose-dependent manner. The new immunoregulatory agents with greater specificity for the immune system, which shows less side effects, will be of great benefit in the treatment of diseases with a pathological immune response as an important component in the disease process. REF: 24435 PREVIOUS TECHNIQUE
The signaling between the cells is to a greater extent, mediated by oligo- or polypeptide Ldos principles, including cytokines, neuropeptides and hormones. A possible form, such as a signal that can be transmitted may involve the activity of the oxidoreductase as measured by the thiol-disulfide interaction of the cysteine residues. This type of action can induce conformational changes of the proteins, which can finally result in a signal to the nucleus of the cell. In this way, redox systems, based on oxidized or reduced cysteines, play important roles in initiating, maintaining and / or deregulating inflammatory responses. The redox systems that are characterized today are the thioredoxin (TR) / thioredoxin reductase (TRR) system (Holmgren et al, 1989, J. Biol. Chem. 264, 13963) and similar systems such as glutaredoxin / glutathione reductase (Bush eller et al., 1992, Biochemistry, 31, 9288) and the disulfide isomerase protein (PDI) systems (Noiva and Lennarz, 1992, J. Biol, Chem., 267, 3553). The TR / TRR system and the related redox systems are potent regulators of different immunological and inflammatory parameters known as the expression of chain α IL-2R (Espinoz-Adelgado et al., 1992, J. Immuno.L., 149, 2961) , modulation of the expression of IFN-gamma activity (Deiss and Kimchi, 1991, Science, 252, 117), differentiation and effector function of lymphocytes (Yodoi and Uchiyama, 1992, Immunol. Today 13, 405-411) , regulation of eosinophil effector functions (Balcewics et al., 1991, J. Immunol., 147, 2170), glucocorticoid receptor activation (Grippo et al., 1985, J. Biol .Chem 260, 93-97) and modulation of the immune response during pregnancy (Clar et al, 1991, J. Reprod. Fert., 93, 525). The active site of TR includes a sequence with a -Cys-Gly-Pro-Cys- motif. The selected virus proteins, for example the products of the gene encoded from the X regions of the human T cell leukemia viruses (Shimotohno et al, 1985, PNAS 82, 302-306) and the human immunoregulatory proteins may have cysteine-containing sequences, which are homologous to such a motif -Cys-Gly-Pro-Cys-. It has been considered that these proteins can either express oxide reductase activity or they can be substrates for such activity or possibly act as inhibitors of such activity. Previously, the peptides based on the sequence of the active site TR rich in cysteine mentioned in the foregoing, have been produced and shown to have biological activities similar to the native protein. Another example of a cysteine-containing peptide with thioredoxin-like activity was obtained from hFSH-β- (81-95) (Grasso et al, 1991, Molecular and Cellular Endocrinology 78, 163). Analogs of humoral thymic gamma2 (THF-gamma2) to be used as immunoregulatory agents in pharmaceutical compositions are described in WO, Al, 9501182 (12.01.95). This document describes two cyclic analogues: Leu-Glu-Cys-Gly-Pro-Cys-Phe-Leu (SEQUENCE OF IDENTIFICATION NO: 34) and Leu-Cys-Ala-Gly-Pro-Cys-Phe-Leu (SEQUENCE OF IDENTIFICATION NO: 35); which are excluded from the present invention. However, this document does not disclose the active importance of cysteine-containing sequences. Peptides have been prepared with cysteine-containing motifs, selected from the structural proteins of the virus, for example retroviral transmembrane protein pl5E and human proteins involved in the regulation of inflammation, for example TGF-β. Then the peptides are modified to obtain optimal immunoregulatory properties.
BRIEF DESCRIPTION DB THE INVENTION
Now surprisingly a new group of peptides has been found, which are excellent as immunorecrulators. The peptides according to the present invention comprise 4-15 amino acids and can be described by the general formula (I):
A - X - Y - Cys - Z - B (I)
wherein X was selected from Gly, Ala, Lie, Asp, Thr, Ser, Arg or Trp; And it was selected from Pro, pipecolic acid (hereinafter called Pee) or lie; Z was selected from lie, Phe, Pro, Ala, Tyr or Gly; A is H, a protecting group, an amino acid either in the L or D form with or without the functionality of the protected side chain and / or the N-terminal protection or an amino acid sequence with or without functionalities of the protected side chain and / or N-terminal protection; B is OH, NH2, a protecting group, an amino acid either in the L or D form with or without the functionality of the protected side chain and ending with an amide at the C-terminus, a free carboxyl or a protecting group or a sequence of amino acids with or without the protected side chain functionalities and ending with a C-terminal amide, a free carboxyl or a protecting group; and with the proviso that the following sequences are excluded from formula (I):
u-Glu-Cys-Gly-Pto-Cy $ -Phc- eu (SEQ ID NO: 34), u-Cy $ -Al »-Gly-Pro-Cy? -Phe.Leu (SEQ ID. NO: 35), Tyt-pc-P. ^ Cy $ -Pte-I ^ Ser-S < r-Uu-Ly $ -Ar | -Lea-Leu-Ile (SEC, FROM IDENTITY NO: 36? Tyt-From-P? t> -Cyt-Phe.Pn S «-S« r-Le? Ly $ -Arj-Lc -De (ID SECTION NO: 37), Ser-Gly.Pto-Cyí-l ^ Ly $ .Ast Gly.Gln-Pro-Ser (SEC. OF I0ENT. N0: 38) and Thr-Pre-Pßo-TItf-l or-Cys-Pro-Ser (SEQ ID NO: 39).
The length of A and B may vary, while the criteria are related to the length and possible amino acids or other substituents are met. The amino acids according to the present invention can be both of the amino acids that occur naturally and unnaturally, synthetic amino acids or amino acid analogues. Examples of the protecting groups for A are a variety of carbamates and amides of which the following protective groups are preferred: acetyl (Ac), 9-fluorenylmethyl carbamate (Fmoc), 1-methyl-1- (4-) carbamate biphenylyl) ethyl (Bpoc), trityl (Trt), allyl carbamate (Alloc) and t-butyl carbamate (Boc). Especially preferred protecting groups for A are acetyl (Ac), 9-fluorenylmethyl carbamate (Fmoc) and t-butyl carbamate (Boc).
Examples of protecting groups for B are a variety of esters such as Ci-C8 alkyl, allyl, adamantyl, benzyl and t-butyl. Also within the scope of the present invention are homodimers according to formulas (II), (III) and (IV)
A »X- Y • CCyyss - ZZ - BB OD A-X-Y Cyi-Z-B
A-X-Y Cy-Z-B (ni) A-X-Y. Yi-Z-B
that is, homodimers of the peptides of the formula (I) according to the invention. Also within the scope of the present invention are pharmaceutically acceptable salts of the peptides of formulas (I), (II), (III) and (IV). The peptides of the formula (I) which contain various cysteine residues may both exist in an oxidized form and in a reduced form. The oxidized form may contain intramolecular disulfide bonds resulting in oxidized monomers or intermolecular disulfides resulting in both dimers from the front to the front and from the front to the back of the peptides of the formula (I). Preferred peptides according to the present invention are peptides of formulas (I), (II), (III) and (IV) in which
X is Gly, Y is Pro and ZesBf, X is G.y, Y is Pro and Z is Gly; Xes Ala, YesProy Z is Ala; X is fit, Y is Pro and Z is Tyr, X is All, Yes Pro and Z is De, Xes Arg, Y «Pro and ZesDt Xes Bt, Y is Pro and Z is He; X is Alp, Yes Pro and Z isDt; X is Trp, Y is Pro and ZesBt; X is Trp, Y is Pro and ZesGrjr, Xs Oy.YtsDt and ZesDe;
X is Gly, Y is ee and Z eslíe; X is Thr. And it is Pro and Z is Tyr, X is Thr, Y is Pee and Z is Phe; X is Ala, Y is Pro and Z ßsphe; X is Ser. And it is Pro and Z is Phe; X is Gly, Y is Pro and Z is Pro; or Xes Gly. And it's Pro and Z is Tyr.
wherein A and B can be varied as defined in the above; and with the proviso that the following sequence is excluded from formulas (I), (II), (III) and (IV): Ser-Gly-Pntp < ^ Pro-Ly > -Asp-Gly ^ l ?? - Pro-Ser (SEC DEI ENT. N0.38).
Preferred peptides according to the invention are
H-Gly-Pro-Cys-neOH (SEC.DEIDEWT.NO: 1): F oc-Oly-I »ro-Cyt-De-OH (SEQ ID NO: I H-aiy-Pro-Cys -Gly-OH (SEQ ID NO: 2): H-Ala-Pro-Cys-Ala-OH (SEQ ID NO: 3): H-De-Pro-Cys-TyrOH (SEC.DEIDENT .N0: 4); H-Trp-Pro-Cy-Gly-OH (SEC.DELTA.N0: 32); H-Pr; and iIy-Pto-Cys-ne-OH (IECENT SEC. ); (SEC.DEIDENT.N0: 6); H Sly-Pr ^ Cys-De> Lee A »-Ari-OH (SEC.DEIDENT.N0: 7, H- ^ Le? Phe ^ y-Pro-Cy »-De-OH (SEQ ID NO: I); H4 ^ L ^ DP!» E ^ y-Pro-Cy? -Ile-OH (SEQ ID NO: S * H-? L ^ ? e-AJ »-Pre-Cy» -De-OH (SEC.DEIDENT.N0:); H-Le? Read Prte-Arf-Pro-Cy »-De-OH (SEQ ID NO: 10); H- u-La »P1? Ev11« vPra-G s-sto-OH (SEQ ID NO: i 1); H-LeiHLa? -Phe-Trp ^ ro ys-Ile ^> H (3EC .DEIDENT.N0: 13)? H-Leu-Leu Phe-Gly-ue-Cys-Ifc-OH (SEC.DEIDENT.NO:14); H- u-cu Phe-GIy.Pec-Cyj-lle.OH (SEC.DEIDENT.NO15); H-AIa-Val-T-Thr-Pro-Cys-Tyr-OH (SEC.DEIDENT.NO:33); H-Tyr-Pne-Tyr-Thr-Pec-Cys -Phe-OH (SEC.DEIDENT.NO: 16); H-Phe-ViJ ^ Met-Alt-Pp? -Cys-Phe-OH (SEC.DEIDENT.NO:17); HU u.l ^ Tyr-Ser-Pro-Cys-Phe.OH (SEC.DEIDENT.NO: 18); H-Ue-Ser íly-Pro-Cys-Pro-Ly »-OH (SEC.DEIDENT.NO:19); (SEC.DElOENT.NO: 20); (SEC.DEIDENT.NO:21) H-Glu-Lys-Gly.Pro-Cy »-Tyt-Ar | -OH (SEC.DEIDENT.NO:22); H-L ^ - * Ptte ÍIy -? »R ^ yvpe-L« u-OH (SEC.DEIDENT.NO:23); H- uL ^ Rie ^ il-Pro ^ í-De-Uu-NH, (SEC.DEIDENT.NO:24): H- u- »Pne ily-Pro-Cy $ -u« -Le? J-OAllyl ( SEC.DEIDENT.NO:23); H-Uu-I ^? Phs 3ly-Pto ^ > ^ -ne- cu.Asn-NH? (SEC.DEIDENT.NO:25): - ü-l ^ \? - Fhe ll 'Pr ^' Ue-Le? -Au ^ An-O (SK DE I ENT N0: 26): Hr ^ I ^ l ^ ^ -Pro-Cs-u ^ l ^? It ^ (SEC.DEIDENT.N0: 27): H-Le * u-Leut »rli * -Gy-Pto-Cyß-D ^ (SEC.DEI0ENT.N0: 28 ); H-Phe-LM4? Ifr ^ l-? O ^ s-s ^ Le? (SEC.DEIDENT.NO:29); Fs * noc-Pr? E? N? -Pl «ay-aai? ^ (SEC.DEIDENTN0: 29); H-nje ^^ l ^^^ ro - ^ 'Pf0-0"< SEC-DE IDEN N0:» *
H-Pl »-ys» u ^ ly-Pto- < ! ^ - Pro-OH (SEC.DEIDENT.NO:31);
H-L «HLeu-Phe-01y-Prt CV» -De ^) H H-tt-Leu -? »He-siy-Pro- < ! ^ Dß-OH (homodimer of SEQ ID NO: I);
(homodimer of SEQ ID NO: 18);
H-Gly-Pro-Cys-De-OH H-Gly-Pro- € ys-Uc-OH (homodfomer of SEQ ID NO: i>;
(homodimer of SEC.DEIDENT.NO: 28);
H-Phß-Cys-u-Gly-Pro-Cyt-Pro-OH H-Phe-Cy. l ^ u-aiy-l'ro-íí ^ s-Pio-f? i (front to front of the horpodimero e the SEC.DEIDENT.N0: 30); Y
H-l ^ tte ^ yt- o ^ íly-Psfc ys-Pro-OH (front part to rear part of the homodimer of SEC. DEIDENT.N0: 30).
Especially preferred peptides according to the invention are peptides of formulas (I), (II), (III) and (IV) wherein
Xes Gly, Yes Pro and Zes Dt; Xes Ata, Yes Pro and Zas Ata; Xes Ala. And it's Pro and Zeslta; XßsAsp, YeßPro and Zas Ib; XesGIy. Yes Üß and ZesTJtí Xßs Gly, Y is Pee and Z is lie; Xes Ser, Y is Pro and Z is Phe; or XesGly, YesPro and Z is Pro;
wherein A and B can be varied as defined in the above; and with the proviso that the following sequence is excluded from the formulas (I), (II), (lil) and (IV): Scr ily-Pro-Cys-i ^ o-Ly »-As? ^ ry-Oto -Pro-Ser (SECDEIDENT.NO 38) The peptides especially preferred according to the invention are the peptides
H ^ ly-Pro-Cys-Ik-OH (SEC.DEIDENT NO: 1); H-Ala-Pro-Cys-Ata-OH (SEC.DEIDENT.N0: 3); H-Phe-Gly-Pro-Cy tvDe-OH (SEQ ID NO: 5); H-Uu-Lcu Phe-Gty-Pro-Cys-De-OH (SEQ ID NO: 8); H.- ^ L ^ - h ^ laro-Cys-Ik-OH (SEQ ID NO: 9Y, H- u-Phe-Asp-Pro-Cys-ne-OH (SEQ ID. NO: 12); H-Leu-Lcu-Fhc-Gly-De-Cys-Ile-OH (SEQ ID NO: 14); (SEQ ID NO: 15); H-Leu-u ^ yr-Ser-Pn ^ ys-Phc-OH (SEQ ID NO: 18); HL ^ - u-Hie ^ l -Pro ^ S'De- u-OH (SEC.DEIDENT NO: 23);
(Homodimer of IDENTIFICATION NO: 8);
H- u-L? U-Tvr-Ser-Pi- Cys-Phe-OH H-L ^ -? Tyr-Sßt-l or-Cy ».Phe-OH (homodimer of SEQ ID NO: 18);
H.Pt?e-Cys-L«n?^ly-Pro-Cys-Prc^ (SEC.DEIDENT.NO:30);
(SEQ ID NO: 1);
(front to front of homodimer of SEQ ID NO: 30); and (part deletes the back of the homodimer of the SEC, DE 1DENT, NO: 30)
The most preferred peptides according to the invention are peptides of the formulas (I), (II), (III) and (IV) wherein
XesGly, YesPro and ZesUe, Xes Ala, Y is Pro and Zes De; X is Being, And is Pro and Zes Phe; or XesGly, Yes Pro Zes Pro;
wherein A and B can be varied as defined in the above; Y
with the proviso that the following sequence is excluded from formulas (I), (II), (III) and (IV): S € r ^ iy-Pio-Cvs-Pro-Lys-Aip-Gíy-Glii-Pro -Ser (SEC. DE HJENT. N0: 38).
The most preferred peptides according to the invention are the peptides
H-Gly-Piv € ys-Ik-OH (SEC.DEIDENT.NO :!); H-Leß-Lea-Plie-aiy-Pro-Cys-De-OH (SEQ ID NO: 1); H-l ^? The «-Phe.Ala-Pro- < : y »-De-OH (SEQ ID NO: 9): H ^ u-Leu-Phc-Ajp-Pro-Cys-De-OH (SEQ ID NO: 12);
H- u- u Tvr-Ser-Pro: yvPhe-OH. { SEC. OE lOENT. NO: 18); H- ?? - L «u-r? E Hy-Pro ^ Ds > Leii-OH (SEC.DEIDENT.NO:23):
H-Lau-Lea-Phe-Gly-Pro-Cys-Oe-CXi H -eu-L < »Phe Jly-Pro-Cy» -IIC-OH (homodimers of SEQ ID NO: 8);
H-Uu- u ^ Tyr-Ser-PiO-Cys-PiTe-OH H- u-? I'Tyr-Ser-s * ^ Cys-PlMV? H (homodimer of SEC DE IDENT, 18); and H-Phe-yy * ?? - Gly-l ^ ys-Pr * > OH (SEQ ID NO: 31).
It has surprisingly been found that the peptides of formulas (I), (II), (III) and (IV) are excellent as immunoregulators, thus having immunostimulatory or immunoinbibrinding effect. The invention in this way provides peptides with advantageous properties for the treatment of diseases where an anergy of the immune response or an aberrant immune response or an ineffective host defense may be suspect. Such diseases include chronic bronchitis, where a reduction in the rate of worsening had previously been reported with immune response modifiers such as Biostim.
(Radermecker, M. et al., Int. J. Immunopharmac., 10, 913-917,
1988; Scheffer, J. et al., Arzneim Forsch / Drug Res. 41, 815-820, 1991), Ribomunyl and Broncho Vaxom (Paupe, J. Respiration 58, 150-154, 1991) as well as with N-acetylcysteine (See Bergstrand, H. et al., J. Free Radie, Biol. Med. 2, 119-127, 1986). Such diseases also include certain forms of malignancies. In this way, numerous research institutes around the world help find ways to stimulate the immune response in patients with various forms of malignancies and numerous reviews in the literature deal with this approach (Stevenson, FK FASEB J 5: 2250-2257, 1991; Melief, CJM Advances in Cancer Research 58: 143-75, 1992; Chen, J. et al., Immunology Today 14:10, 483-86, 1993). To mention some example patients with intracranial tumors (gliomas) present a profound decrease in immunity, possibly due to a defect in the secretion of IL-2 as well as expression of IL-2 receptors in the T cells of these patients
(Rosz an, T. et al., Immunology Today 12, 370-374, 1991).
In addition, a significant adjuvant effect in the immunotherapy of melanoma and colon carcinoma has been documented by the Levamisole immunostimulator (Van auwe, J. and Janssen, PAJ: Int. J. Immunopharmac 13, 3-9, 1991) and immunotherapy with IL. -2 in vivo or treatment of patients with killer cells activated by lymphokine with IL-2 ex vivo has caused the regression of cancer in selected patients
(Rosenberg, S.A. Immunology Today 9, 58-62, 1988). Malignant diseases where the peptides of the formulas (I),
(II), (I "I) and (IV) can be expected to have advantageous effects, including tumors of mesenchymal origin such as sarcomas such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma or cordosarcoma, sarcomas similar to angiosarcoma, endotheliosarcoma, lymphangiosarcoma, synovium.rcoma or mesotheliomas, leukemias and lympholas similar to granulocytic leukemia, monocytic leukemia, lymphocytic leukemia, malignant lymphoma, plasmacytoma, sarcoma of the cellular reticulum or Hodgkins disease, sarcomas similar to leiomisarcoma or rhabdomysarcoma, tumors of epithelial origin (carcinomas) such as squamous cell carcinoma, basal cell carcinoma, carcinoma of the gland salivary, carcinoma of the sebaceous gland, adenocarcinoma, papillary carcinoma, papillary adenocarcinoma, cystadencarcinoma, medullary carcinoma, carcinoma s? n differentiate, bronchogenic carcinoma, melanoma, renal cell carcinoma, liver-hepator cell carcinoma, carcinoma of the bile duct cholangiocarcinoma, papillary carcinoma, transitional cell carcinoma, squamous cell carcinoma, choriocarcinoma, semonoma or embryonal carcinoma, tumors of the central nervous system such as glioma, meningoma, medulloblastoma, schwannoma or ependymoma. In addition, the peptides according to the present invention also have advantageous properties for the treatment of chronic infections such as herpes, aphthous stomatitis and minimal change syndrome where the clinical improvement had previously been reported by the treatment by an immunostimulator such as Levamisole as well as well as other chronic inflammatory diseases in the urinary tract or in the ear, nose or throat, whose benefit is treatment with immunostimulants such as Biostim, Broncho-Vaxom and Ribomunyl, or in HIV infection or AIDS. In addition, a damage, defect or imbalance of the immune response has also been postulated to exist in topical diseases such as atopic dermatitis, rhinitis and asthma (Katz, D.H. Immunology Rewie s 41, 77-108, 1977). Since theoretical considerations suggest that the stimulation of an immune response would possibly be the best way to restore imbalances and autoimmunity (Varela, FJ. "And Cout: .nho, A. Immunology Today 12, 159-166, 1991), the peptides can also be expected to have advantageous properties for the treatment of asthma, rhinitis, atopic dermatitis and autoimmune diseases such as non-obese diabetes, systemic lupus erythematosus, scleroderma, Sjögren's syndrome, dermatomyositis or multiple sclerosis, rheumatoid arthritis and possibly psoriasis. the peptides according to the present invention, due to their immune modulating properties, may have advantageous properties as adjuvants in various forms of vaccine preparations.Due to their immune modulating properties, the peptides may also be expected to have favorable properties in inhibit the rejection of organs / transplants.
Finally, the peptides according to the present invention can be expected to have advantageous properties in the treatment of arteriosclerosis, whether or not they will influence an inflammatory process assumed in this condition (Hansson, GK et al., Proc. Nat. Acad. Sci. USA 88, 10530, 1991). The peptides according to the present invention are particularly suitable for the treatment of malignancies such as melanoma, mammary carcinoma, gastrointestinal carcinoma, glioma, carcinoma of the bladder and squamous cell carcinoma of the neck and the region of the head; infections such as chronic bronchitis, hepatitis, post-infection anergy and acquired immune deficiencies such as AIDS; post-traumatic immunological anergy; and autoimmune diseases involved such as rheumatoid arthritis, multiple sclerosis, arteriosclerosis and psoriasis.
Preparation
The peptides according to the present invention can be prepared using the standard solid-phase sequential coupling technique using an automatic peptide synthesizer (see, for example, Jones, J. The Chemical Synthesis of Peptides, pp. 132-156, first edition). , Oxford University Press, 1991 and R. Epton (ed) Innova ion and Perspectives in Solid Phase Synthesis, SPCC (UK) Ltd, 1990). The preparation starts from the amino acid C-terminatl, which can be obtained grafted to a methylbenzene: hydrylamine, benzhydrylamine or chlormethylated resin or other suitable solid support. The other amino acids are grafted step by step, after their side chains have been protected. In this coupling method, the a-amino groups of the amino acids are protected with either the Fmoc or t-Boc methodology. Protective groups for amino acid side chains are well known in the art. The complete protected peptide is released either from the chloromethylated resin by ammoniolysis to obtain the protected amide, or from the methylbenzhydrylamine or benzhydrylamine resins by acidolysis. The peptides according to the invention can be prepared using methods in solution, either by stepwise or fragment condensations (see for example: Jones, J. The Chemical Synthesis of Peptides, pp. 115-131, first edition, Oxford University Press , 1991). A protected alpha amino amino acid is coupled to an appropriately protected alpha carboxyl amino acid (such protection may not be required depending on the chosen coupling method) using diimides, symmetric or asymmetric anhydrides, or other coupling reagents or techniques known to those skilled in the art. . These techniques can be either chemical or enzymatic. The alpha amino and / or alpha carboxyl protecting groups are removed and the next appropriately protected amino acid or amino acid block is coupled to extend the growing peptide. Various combinations of protective groups and chemical and / or enzymatic techniques and assembly strategies can be used in each synthesis. The dimers (peptides of formulas (II), (III) and
(IV)) and the peptides containing intramolecular disulfide bonds between the cysteine residues, can be prepared by general oxidation techniques described by Andreu et al. In Methods in Molecular Biology, Peptide Synthesis Protocols vol 35 (Humana Press Inc., Totowa, NJ , 1994) and Ruiz-Gayo et al, 1988, Tetrahedron Letters, 29, 3845-3848, as well as in other reference works known to those skilled in the art. The determinations of the mass spectra of low resolution and exact mass were recorded in Autospec-Q, Fisons Analytical, instrument of sector of double approach equipped with an interface LSIMS.
DETAILED DESCRIPTION OF THE INVENTION
The invention will now be described in greater detail with the following examples, which should not be considered as limiting the invention.
Example 1
Synthesis of H-Gly-Pro-Cys-Ile-OH (SEQUENCE OF IDENTIFICATION NO: 1) One resin (0.37 g, 0.22 mequiv / g, 81 μmoles) consisting of a cross-linked polystyrene backbone grafted with polyethylene glycol chains, functionalized with the p-hydroxymethylphenoxyacetic acid linker (Sheppard and Williams, 1982, Int. J. Peptide Protein Res., 20, 451- 454) and Fmocte from Rapp Polymere (Germany) was used for the synthesis of the amino acids Na-Fmoc were from Bachem (Switzerland) and Cys was: protected with a triphenylmethyl group (Trt). The DMF was distilled before being used. The Na-Fmoc amino acids were attached to the peptide-resin as esters 7-aza-1-benzotriazolyl (HOAt) (Carpino, 1993, J. Am. Chem. Soc. 115, 4397-4398). These were prepared, in itself, in the peptide synthesizer of the appropriate amino acid Na-Fmoc (0.32 mmol) and HOAt (65 mg, 0.48 mmol) by the addition of DMF (0.5 ml) and a solution of 1,3-diisopropyl -carbodiimide in DMF (0.39 M, 0.8 ml, 0.312 mmol). After 45 minutes bromophenol blue (Flegel and Sheppard, 1990, J. Chem. Soc., Chem. Commun. 536-538) in DMF (0.15 mM, 0.4 ml) is added to the HOAt ester by the synthesizer and the resulting solution It is recirculated through the column. The acylation was monitored (Flegel and Sheppard, 1990, J. Chem. Soc., Chem. Commun. 536-538) using the absorbance of bronphenol blue at 600 nm and when the coupling was complete, the peptide-resin was automatically washed with DMF. The coupling times for the different N ^ -Fmoc amino acids were approximately 30 minutes. Deprotection of Na-Fmoc from the peptide-resin was performed by a flow of 20% piperidine in DMF through the column for 12.5 minutes and monitored (Dryland and Sheppard, 1986, J. Chem. Soc. Perkin Trans. I , 125-137) using the absorbance of the dibenzofulvene-piperidine adduct at 350 nm. After the deprotection of N-^ - Fmoc was terminated, the peptide-resin was again automatically washed with DMF. After the end of the synthesis and unfolding of the N-terminal Na-Fmoc group, the resin was washed with dichloromethane (5 x 5 ml) and dried under vacuum. The peptide (40 μmol) is then cleaved from the resin (200 mg) and the side chains of amino acids were deprotected with the treatment with trifluoroacetic acid-water-thioanisole-ethanedithic (87.5: 5: 5: 5: 2.5, 20 ml) for 2 h followed by
Example 34
Synthesis of H-Leu-Leu-Phe-Gly-Pro-Cyvpe-OH H- u.l? -Pbe-Gly-Pro-Cy »-I] e-OH (homodimer of SEQ ID NO: 8)
A solution of the monomer (1.5 mg / ml in 50 nM phosphate buffer, pH = 7.2) containing 5 ppm of copper (II) sulfate is stirred at room temperature for 20 hours. The solution is lyophilized and redissolved - in water / acetonitrile (80/20) and purified by reverse phase CLAP using a C-18 VYDAC column (5 μm, 4-250 mm). An aqueous solution containing 0.1% trifluoroacetic acid and 5% acetonitrile was used as a mobile phase. The acetonitrile concentration was linearly increased to 60% for a measured time of 25 minutes. The flow rate was 1.5 ml / minute and the components were detected with UV at 220 nm. The fractions were collected manually and verified with FAB-EM. Repeated injections were collected to give a solution of the product, which was lyophilized. FAB-MS: 1521 (MH +). The compound is listed in Table 1.
Examples 35-37
The peptides according to Examples 35-37 were prepared using the same protocol as in Example 34. The compounds are listed in Table 1.
Example 38
The peptide according to Example 38 was prepared using the same protocol as in Example 1. The compound is listed in Table 1.
Example 39
The peptide according to Example 39 was prepared using the same protocol as in Examples 34-37. The compounds are listed in Table 1.
Examples 40-41
The peptides according to Examples 40-41 were prepared using the same protocol as in Example 1. The compounds are listed in Table 1.
Example 42
Synthesis of H-Phe fr u ^ ly- ^ C s-Pro-OH (front to front of homodimer of SEC DEIDEHT NO: 30)
To prepare the parallel homodimer (front to front) a single peptide chain with a protective group Acm (acetamidomethyl) on one of the cysteines and with the other unprotected cysteine (H-Phe-Cys-Leu-Gly-Pro- Cys (Acm) -Pro-OH) was synthesized using the same protocol as in example 1. The monomer was dimerized by the oxidation of the free cysteines using the same protocol as in example 2. The second disulfide bond was made using the Ruiz-Gayo protocol (Ruiz-Gayo et al, 1988, Tetrahedron Letters, 29, 3845-3848) in which the deprotection of a single vessel and the oxidation of cysteine protected with mAb with iodine in 80% aqueous acetic acid resulted in an unpurified product which was purified in CLAP. The compound is listed in Table 1.
Example 43
Synthesis of frPl? C-Cvs-Le ^ ly «> Pj £ ys-P ?? - OH (front part of the back of the homodimer of ID SECTION NO: 30)
To prepare the antiparallel homodimer (from the front to the back), Ruiz-Gayo's general procedure was used (Ruiz-Gayo et al, 1988, Tetrahedron Letters, 29, 3845-3848). Two chains of individual peptides each with a protective group Acm (acetamidomethyl) in one of the cysteines and with the other unprotected cysteine (H-Phe-Cys-Leu-Gly-Pro-Cys (Acm) -Pro-OH and H-Phe-Cys (Acm) -Leu-Gly-Pro-Cys-Pro-OH) was synthesized using the same protocol as in Example 1. The unprotected cysteines in one of the monomers was activated with dithiopyridine resulting in the S-pyridyl derivative of H-Phe-Cys (SPyr) -Leu-Gly-Pro-Cys- (Acm) -Pro-OH. This derivative was reacted with the second peptide chain resulting in the first disulfide. The second disulfide bond was made using the same protocol as in Example 42 with iodine in 80% aqueous acetic acid which, after purification in CLAP, resulted in: the final product. The compound is listed in Table 1.
The following Table 1 lists the compounds according to the invention and their identification by the FAB-MS spectra.
Table 1
34 H- u-Leu-Phe-Gly-Pro-Cy »-Ile-OH 1521 H« Leu-Leu-Phe 31y-Prc-Cys-Jc-OH (homodimer of SEQ ID NO: 8) 35 HL? U-Leu-Tyr-Ser-Pro-Cyi-Phe-OH 1682
H-Leu-? T r »Ser-fto Vs-Pl? E-OH (homodimer of SEQ ID NO: 18) 36 H-Gly-Prc-Cys-De-OH 775 H-Gly-Pro -Cys-pe-OH (homodimer of SEC.DEIDENT.NO: 1) 37 H-Phe-Let > -Pre-Gly-Prc-pe-Leu-Asn-3101 H-Phet-Phe-Qy-Pro-c ^ s-De-Lett-Asn-Arf-Leo-Met-Glu-NH,? Rg- Leu-Met-Glu-NHs (homodimer of SEQ ID NO: 29) 38 H ihc: y- L-5 «-Gly-Pro-Cys-Pro-OH 736
(SEC.DEIDENT.NO: 30) 39 734
H-Phe-Cyi-Le-i lly-Pio-Cys-Pro-OH (SEC.DEIDENT.NO: 31)
40 H-Gly- or-Cys-Oe4 u-Asn-Ar | -OH 772
(SEC.DEIDENT.NO: 7)
41 H-u-Ptae-Gly-Pr-yi-u Leu-Asri-Arf-1146 OH (SECDEIDENT.NO: 26)
42 H-Phe-Cy »- u Hy-Pro-CyvPro-OH 1467.7
H-Pt * e-Cy * -Uu-G-y-Pro- »-P? O-OH (front to front of homodirnerode SEC ID. NT.110: 30)
Pharmaceutical preparations
The peptides according to the invention can be administered orally, nasally, rectally, intravenously or by inhalation. The dose will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when it determines the regimen and individual dose level as the most appropriate for a particular patient. The pharmaceutical preparations comprising the peptides according to the invention can conveniently be tablets, pills, capsules, syrups, powders or granules for the oral administration of sterile parenteral solutions or suspensions for parenteral administration or suppositories for rectal administration. For the preparation of pharmaceutical preparations containing a peptide according to the present invention in the form of dosage units for oral administration, the active peptide can be mixed with an adjuvant or a carrier, for example lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatin or polyvinylpyrrolidone and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin and the like and then compressed in tablets. If coated tablets are required, the cores prepared as described above, may be coated with a concentrated sugar solution, which may contain for example gum arabic, gelatin, talcum, titanium dioxide and the like. Alternatively, the tablet can be coated with a polymer known to the man skilled in the art, dissolved in an easily volatile organic solvent or a mixture of organic solvents. The edible dyes can be added to these coatings to easily distinguish between tablets containing different active substances or different amounts of the active peptides. For the preparation of soft gelatin capsules, the active substance can be mixed, for example, with a vegetable oil or polyethylene glycol. The hard gelatine capsules may contain granules of the active substance using either the excipients for tablets mentioned above, for example lactose, sucrose, sorbitol, mannitol, starches (for example potato starch, corn starch or amylopectin), the cellulose derivatives or gelatin. Also liquids or semi-liquids of the drug can be filled into hard gelatin capsules. The dosage units for rectal application may be solutions or suspensions, or they may be prepared in the form of suppositories comprising the active substance in admixture with a neutral fat base, or rectal gelatin capsules comprising the active substance in admixture with vegetable oil or paraffin oil. Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing a peptide as described herein as the active substance, the remainder being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose as a thickening agent or other excipients known to man skilled in the art. Solutions for parenteral applications by injection can be prepared in an aqueous solution of a pharmaceutically acceptable, water-soluble salt of the active substance. These solutions may also contain stabilizing agents and / or buffering agents and may involve the use of surface active agents to improve solubility. Conveniently they can be provided in several dose unit vials. The compounds according to the invention can be formulated in pressurized metered dose inhalers or dry powder inhalers for oral or nasal inhalation or in liquid formulations for nebulization. The active substance is micronized or processed in any other form at particle size suitable for inhalation therapy (mean mass diameter <4 μm). For metered dose inhalers, the micronized substance is suspended in a liquid propellant or a mixture of liquid propellants, which can also act as solvents and fill in a container, which is equipped with a metering or metering valve . The propellants used can be hydrofluoroalkanes (HFA) of different compositions. The most frequently used HFAs are tetrafluoroethane (propellant 134a) and heptafluoropropane (propellant 227). Low concentrations of surfactants such as sorbitan trioleate, lecithin, oleic acid or other suitable substances can be used to improve the physical stability of the preparation. Ethanol or other solvents can be used to increase the solubility of the substances in the propellants.
The active substance can also be supplied by means of a portable inhaler device, suitable for inhaling dry powder. The active substance can be used alone or combined with a suitable carrier substance such as lactose, mannitol or glucose. Other additives may also be included in the powder formulation for various reasons, such as to increase stability. The inhaler can be a single dose inhaler with a presumed dose or a multiple dose inhaler, in which the dose is created by a dosage unit inside the inhaler or is supplied from a presumed dose assembly.
Biological studies
The ability of the peptides according to the invention to modulate immune responses can be illustrated by their effectiveness in the late-type hypersensitivity test in animals (DTH) in mice. Both male and female Balb / c mice, obtained from
Bomholtsgaard (Denmark) were used with a weight of 18-20 grams. 4-Ethoxymethylene-2-phenyloxazolin-5-one (OXA) (England) and served as the antigen in this test.
The mice were sensitized, Day 0, by epicutaneous application of 150 μl of an absolute ethanol-acetone (3: 1) solution containing 3% OXA on the shaved abdomen. Treatment with the peptide or vehicle (0.9% NaCl) was initiated by oral feeding immediately after sensitization once a day continuously until Day 6. Seven days (Day 6) after sensitization, both ears of all mice were stimulated on both sides by the topical application of 20 μl of 1% OXA dissolved in peanut oil. The thickness of the ear was measured before and 24 or 48 hours after the stimulation using the Oditest spring gauge. The stimuli and measurements were performed under light pentobarbital anesthesia. The intensity of the DTH reactions was expressed according to the formula: tt24 / 48"tt0 ^ m in units, where tO, t24 and t48 represent the thickness of the ear before and 24 or 48 hours after the stimulus respectively, in individual tests (T) The result was expressed as the mean +/- SEM The level of significance between the means of the groups was obtained by the two-tailed Student's t-test The immunoregulatory effect of the peptide is reflected in a significant difference in the increase or decrease in the thickness of the ear when compared to the control.
Discussion
The present invention describes peptides that can be expected to have favorable effects for the treatment of various diseases, which affect the immune system including diseases where an anergy of the immune response, an aberrant immune response or peripheral tolerance to pathogens or a deficiency of the ineffective guest for other reasons may be suspect. These types of drugs have an urgent need in the market, instead of or as a complement to more toxic current drugs, for the treatment of many diseases.
Abbreviations Pee pipecolic acid Ac acetyl Fmoc carbamate 9-fluorenylmethyl Bpoc carbamate 1-methyl-l- (4-biphenylyl) ethyl Trt trityl Alloc carbamate allyl Boc carbamate t-butyl FAB-EM fast atom mass-bombardment spectroscopy
DTH late type hypersensitivity OXA 4-ethoxymethylene-2-phenyloxazolin-5-one Acm acetamidomethyl LIST OF SEQUENCES
(1) GENERAL INFORMATION: (i) APPLICANT: (A) NAME: ASTRA AB (B) STREET: Vaestra Maelarehamnen 9 (C) CITY: Soedertaelje (E) COUNTRY: Sweden (F) ZIP CODE: S-151 85 (G) TELEPHONE: + 46-8-553 260 00 (H) TELEFAX: + 46-8-553 288 20 (I) TELEX: 19237 astra s (ii) TITLE OF THE INVENTION: New Peptides with immunoregulatory effects (iii ) NUMBER OF SEQUENCES: 39 (iv) READING FORM ON THE COMPUTER: (A) TYPE OF MEDIA: Soft disk (B) COMPUTER: compatible with an IBM PC (C) OPERATING SYSTEM: PC-DOS / MS-DOS ( D) SOFTWARE: PatentIn Relay # 1.0, Version # 1.30 (EPO) (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: SE 9403526-8 (B) SUBMISSION DATE: OCTOBER 14, 1994 (2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 1: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ii :.) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..4 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 1
Gly Pro Cys He 1
(2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 2: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..4 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 2
Gly Pro Cys Gly 1
(2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 3: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..4 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 3
Ala Pro Cys Ala 1
(2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 4: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ! FEATURE: (A) NAME / KEY: Peptide (B) LOCATION: 1..4 (xi: SEQUENCE DESCRIPTION: SEQ ID NO: 4
He Pro Cys Tyr 1
(2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 5: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..5 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 5
Phe Gly Pro Cys He 1 5
(2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) CHAIN FORM: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..6 (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 6 (D) OTHER INFORMATION: / product? = "OTHER" / note = "Asn-NH2" (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO 6
Gly Pro Cys He Leu Xaa 1 5
(2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 7: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (xi; SEQUENCE DESCRIPTION: SEQ ID NO: 7
Gly Pro Cys He Leu Asn Arg 1 5
(2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 8: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 8:
Leu Leu Phe Gly Pro Cys He 1 5
(2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 9: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 9:
Leu Leu Phe Ala Pro Cys He 1 5
(2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 10: - (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear ( ix) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 10
Leu Leu Phe Arg Pro Cys He 1 5
(2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 11: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 11
Leu Leu Phe He Pro Cys He 1 5
(2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) CHAIN FORM: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 12
Leu Leu Phe Asp Pro Cys He 1 5 (2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 13: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN : (D) TOPOLOGY: linear (ix) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 13
Leu Leu Phe Trp Pro Cys He 1 5
(2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 14: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 14 Leu Leu Phe Gly He Cys He 1 5
(2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 15: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 5 (D) OTHER INFORMATION: / product = " ANOTHER "/ note =" pipecolic acid "(xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 15
Leu Leu Phe Gly Xaa Cys He 1 5
(2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 16: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 5 (D) OTHER INFORMATION: / product = " ANOTHER "/ note =" pipecolic acid "(xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 16
Tyr Phe Tyr Thr Xaa Cys Phe 1 5
(2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 17: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 17
Phe Val Met Ala Pro Cys Phe 1 5
(2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 18: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 18:
Leu Leu Tyr Ser Pro Cys Phe 1 5
(2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) CHAIN FORM: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 19
I Am Gly Pro Cys Pro Lys 1 5
(2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 20: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 20
Phe Leu Fhe Gly Pro Cys He 1 5
(2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 21: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (ix) CHARACTERISTICS: (A) NAME / KEY: Modified site (B) LOCATION: 7 (D) OTHER INFORMATION: / product = " Another "/ note =" Leu-NH2"(xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 21
Leu Phe Gly Pro Cys He Xaa 1 5
(2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 22: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) CHAIN FORM: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 22
Leu Lys Gly Pro Cys Tyr Arg 1 5
(2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 23: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..8 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 23
Leu Leu Phe Gly Pro Cys He Leu 1 5
(2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 24: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..8 (ix) CHARACTERISTICS: (A) NAME / KEY: Modified site (B) LOCATION: 8 (D) OTHER INFORMATION: / product = " Another "/ note =" Leu-NH2"(xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 24
Leu Leu Fhe Gly Pro Cys He Xaa 1 5
(2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 25: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..9 (ix) CHARACTERISTICS: (A) NAME / KEY: Modified site (B) LOCATION: 9 (D) OTHER INFORMATION: / product = " Another "/ note =" Asn-NH2"(xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 25
Leu Leu Phe Gly Pro Cys He Leu Xaa 1 5
(2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 26: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 10 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..10 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 26
Leu Leu Fhe Gly Pro Cys He Leu Asn Arg 1 5 10
(2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 27: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..9 (ix) CHARACTERISTICS: (A) NAME / KEY: Modified site (B) LOCATION: 9 (D) OTHER INFORMATION: / product = " Another "/ note =" Asn-NH2"(xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 27
Phe Leu Phe Gly Pro Cys He Leu Xaa 1 5
(2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 28: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 13 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..13 (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 13 (D) OTHER INFORMATION: / product = " Another "/ note =" Glu-NH2"(xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 28:
Leu Leu Phe Gly Pro Cys He Leu Asn Arg Leu Met Xaa 1 5 10
(2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 29: _ (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 13 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear ( ix) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..13 (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 13 (D) OTHER INFORMATION: / product = "Other" / note = "Glu-NH2" (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 29 Phe Leu Phe Gly Pro Cys He Leu Asn Arg Leu Met Xaa 1 5 10
(2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 30: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 30
Phe Cys Leu Gly Pro Cys Pro 1 5
(2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 31: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: circular (ix) ) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (ix) CHARACTERISTICS: (A) NAME / KEY: Disulfide bond (B) LOCATION: 2..6 (xi) DESCRIPTION OF THE SEQUENCE : SEC. FROM IDENT. NO: 31
Phe Cys Leu Gly Pro Cys Pro 1 5
(2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 32 :. (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTICS: (A) ) NAME / KEY: Peptide (B) LOCATION: 1..4 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 32:
Trp Pro Cys Gly 1
(2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 33: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ii) ) TYPE OF MOLECULE: peptide (ix) CHARACTERISTIC: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 33
Wing Val Trp Thr Pro Cys Tyr 1 5
(2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 34: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: circular (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 34
Leu Glu Cys Gly Pro Cys Phe Leu 1 5 (2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 35: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: circular (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 35
Leu Cys Ala Gly Pro Cys Phe Leu 1 5
(2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 36: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 36
Tyr He Pro Cys Phe Pro Being Ser Leu Lys Arg Leu Leu He 1 5 10
(2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 37: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 13 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 37
Tyr He Fro Cys Phe Pro Ser Ser Leu Lys Arg Leu He 1 5 10
(2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 38: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 11 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 38
Be Gly Pro Cys Pro Lys Asp Gly Gln Pro Ser 1 5 10
(2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 39: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 3
Thr Pro Fro Thr Pro Cys Pro Ser 1 5
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:
Claims (46)
- CLAIMS 1. A homodimer, of a peptide characterized in that it comprises 4-15 amino acids, in accordance with formulas (II), (III) or (IV) wherein X was selected from Gly, Ala, He, Asp, Thr, Ser, Arg or Trp; And it was selected from Pro, Pee or Lie; Z was selected from He, Phe, Pro, Ala, Tyr or Gly; A is H, a protective group, an amino acid either in the L or D form with or without the functionality of the protected side chain and / or the N-terminal protection or a sequence, of amino acids with or without functionalities of the side chain protected and / or N-terminal protection; B is OH, NH2, a protecting group, an amino acid either in the L or D form with or without the functionality of the protected side chain and ending with an amide at the C-terminal, a free carboxyl or a protecting group or a sequence of amino acids with or without the protected lateral chain functions and ending with a C-terminal amide, a free carboxyl or a protecting group; The length of A and B may vary, while the criteria are related to length and possible. amino acids are met; and as well as their pharmaceutically acceptable salts of homodimers of the formula (II), (III) or (IV), for use in the therapy.
- 2. The homodimer according to claim 1, characterized in that XesGly.YesPro and Zes Be; XesOly, YesPro and Zesßly; XesAla, YesPro and ZesAli; Xes De, Yes Pro and ZesTyr; Xes Ala, YesPro and Zeslfe Xes Ai |, Yes Pro and Z eslíe; Xes De. Yes Pro and ZesBe; Xes? Sp, YesPro and ZesQe: XesT, YesPro and ZesDe; Xes Trp. YesPro and ZesGly: XesGly.Yes De and ZesQe; XesGly, YesPec and ZesDß: XesThr, YesPro and ZesTyr, Xest .YesPoc and ZesFhe; Xes Ata, esPro and ZesPfae XesSß, YesPro and ZesPh Xes < Hy. YesPlo and ZesPpso XesOly.YesPro and ZesTyi; to be used in therapy.
- 3. The homodimer according to claim 1, characterized in that XesGly, YesPro and ZesQe; XesAJa, YesPro and ZesDe; Xes Arg, YesPro and Zes De; XesAsp, YesPro and Zes De XesTrp, YesPro and Zes De; Xes Ser. YesPro and Z is Pas or XesGly, YesPro and Zes Pro; to be used in therapy.
- 4. The homodimer according to any of claims 1, 2 and 3, characterized in that A is H, a protective group selected from Ac, Fmoc, Bpoc, Trt, Alloc and Boc, an amino acid either in the L or D form selected from Phe, Leu, Met, Ser, Lys or Tyr with or without it. functionality of the protected side chain and / or the N-terminal protective group selected from Ac, Fmoc, Bpoc, Trt, Alloc and Boc or an amino acid sequence with or without functionalities with either Phe, Leu, Met, Ser, Lys or Tyr e. the lateral C-terminal of the sequence, with or without the functionalities of the protected side chain and / or the N-terminal protective group selected from Ac, Fmoc, Bpoc, Trt, Alloc and Boc; and B is OH, NH2 a protective group selected from alkyl of -CG, allyl, adamantyl, benzyl and t-butyl, an amino acid either in the L or D form selected from Leu, Lys or Arg with or without the functionality of the protected side chain and ending with a C-terminal amide, a free carboxyl or a protecting group selected from C1-Ce alkyl, allyl, adamantyl, benzyl and t-butyl or an amino acid sequence with or without the functionalities either Leu , Lys or Arg at the N-terminal side of the sequence, with or without the functionalities of the protected side chain and terminating with a C-terminal amide, a free carboxyl or a protecting group selected from Ci-C8 alkyl, allyl , adamantyl, benzyl and t-butyl, to be used in therapy.
- 5. The homodimer according to any of claims 1, 2, 3 and 4, for use as an immunoregulatory agent.
- 6. The use of a conformity homodimer cor. any of claims 1, 2, 3 and 4 for the manufacture of a medicament with immunoregulatory effect.
- 7. The use of a homodimer according to any of claims 1, 2, 3 and 4 for the manufacture of a medicament for oral administration.
- 8. A method for immunoregulation, whereby an effective amount of a homodimer according to any of claims 1, 2, 3 and 4 is administered to a host in need of immunoregulation.
- 9. A peptide characterized in that it comprises 4-15 amino acids in accordance with formula (I) A - X - Y - Cys - Z - B (I), in which XesGly, Yes Pro and Zes Des XesGly, Yes Pío and ZesGly: XesAla, Yes ro and Zes Ata; Xes He, Y is Pro and ZesTyp XesAla, TßsPro and Z eslía; XesArf, Yes Pro and ZesDe; Xes De, Yes Pro and Zes De; Xes Asp, YesPro and ZesDe; XesTrp. YesPro and ZesDe; XesTtp, YeßPro and Ze Oly; XesGly. Yes De and Z is De; XesGly. Yes Pee and Z is De; XesTr. Yes Pro and Z is Tyr; XesThr, Yes Pee and Z esPhc; XesAJa. Yes Pro and Z esPhe; Xes Ser. Yes ro and Z esPhe; Xes Gly »Yes Pro and Zes Pro; or XesGly. And it is. Pro and ZesTyr. A is H, a protecting group, an amino acid either in the L or D form with or without the functionality of the protected side chain and / or the N-terminal protection or an amino acid sequence with or without functionalities of the protected side chain and / or N-terminal protection; B is OH, NH2, a protecting group, an amino acid either in the L or D form with or without the functionality of the protected metallic chain and ending with an amide at the C-terminus, a free carboxyl or a protecting group or a amino acid sequence with or without the protected side chain functionality3 and ending with a C-terminal amia, a free carboxyl or a protecting group; the length of A and B may vary, while the criteria are related to the length and possible amino acids are met; and wherein the peptides of the formula (I) containing various cysteine residues may both exist in an oxidized form and in a reduced form, wherein the fora.j. Oxidized may contain intramolecular disulfide bonds resulting in oxidized monomers; as well as their pharmaceutically acceptable salts; and with the proviso that the following sequences are excluded from formula (I): Asp-Pro-Cys-He-He, for use in therapy.
- 10. The peptide according to claim 9, characterized in that the following sequence is excluded from formula (I): Ser-Gly-Pro-Cys-Pro-Lys-Asp-Gly-Gln-Pro-Ser, to be used in therapy. eleven . The peptide according to any of claims 9 and 10, characterized in that XesGly. Yes Pro and Z esOe; XesAla, Yes Pro and Z eslíe; XesArf, Yes Pro and Z is De; XesAtp, Yes Pro and Z is De; Xes Trp, Yes Pro and Z esOe; XesSer, Yes Pro and Z is Pfcej or XesGly, Yes Pro and Z espro; to be used in therapy. 12. The peptide according to any of claims 9, 10 and 11, characterized in that A is H, a protective group selected from Ac, Fmoc, Bpoc, Trt, Alloc and Boc, an amino acid either in the selected LD form of Phe, Leu, Met, Ser, Lys or Tyr with or without the functionality of the protected side chain and / or the N-terminal protective group selected from Ac, Fmoc, Bpoc, Trt, Alloc and Boc or an amino acid sequence with or without functionalities with either Phe, Leu, Met, Ser, Lys or Tyr at the C-terminal side of the sequence, with or without the functionalities of the protected side chain and / or the N-terminal group selected from Ac, Fmoc, Bpoc, Trc, Alloc and 3oc; and B is OH, NH2, a protecting group selected from C -] _ - C, allyl, adamantyl, benzyl and t-butyl alkyl, an amino acid either in the L or D form selected from Leu, Lys or Arg with or without the functionality of the protected side chain and ending with a C-terminal amide, a free carboxyl or a protective group selected from C- ^ - Cg alkyl, allyl, adamantyl, benzyl and t-butyl or an amino acid sequence with or without the functionalities either Leu, Lys or Arg at the N-terminal side of the sequence, with or without the functionalities of the protected side chain and terminating with a C-terminal amide, a free carboxyl or a protecting group selected from alkyl of C1-C8, allyl, adamantyl, benzyl and t-butyl, for use in therapy. 13. A peptide characterized in that it comprises 4-15 amino acids in accordance with formula (I) A - X - Y - Cys - Z B (I), in which XesGly, Yes Pro and Z esDe; XesGly. Yes Pro and Z is Gly; Xes Ale, r * es ro and Z esAs; Xes De, Yes ro and Z is Tyr. Xes Ata. ' Tes Pro and ZesDe; Xes Arg, Yes Pro and Z esDe; Xes De, Yes PTO and Z esDe: Xes Asp, Yes Pro and Z esDe; XesTrp, YesPro and ZesDe; XesTrp.Vßs Pro and ZesGly; XesGly, is De and ZesDe; XesGly.YesPec and ZesDe; X is Thr. And it's Pro and Z is Tyr; XesThr, V is Pee and ZesPhe; X is Alt, r * is Pro and ZesPhe; Xes Ser, Y espro and ZesPhe; X is Gly, YesPro and ZesPro, or Xes Gly, Yes Pro and ZesTyr; A is H, a protective group, an amino acid either in the L or D form with or without the functionality of the protected side chain and / or the N-terminal protection or a sequence, of amino acids with or without functionalities of the side chain protected and / or N-terminal protection; B is OH, NH2, a protecting group, an amino acid either in the L or D form with or without the functionality of the protected side chain and ending with an amide in the C-terminal.l, a free carboxyl or a protecting group an amino acid sequence with or without the protected side chain functionalities and ending with a C-terminal amide, a free carboxyl or a protecting group; the length of A and B may vary, while the criteria are related to the length and possible amino acids are met; and wherein the peptides of the formula (I) that it contains. several cysteine residues may exist both = ~ one form, oxidized and in a reduced form, wherein the oxidized form may contain intramolecular disulfide bonds resulting in oxidized monomers; as well as their pharmaceutically acceptable salts; to be used as an immunoregulatory agent. 14. The peptide according to claim 13, characterized in that the following sequence is excluded from the formula (I): Asp-Pro-Cys-He-He, to be used as an immunoregulatory agent. 15. The peptide according to any of claims 13 and 14, characterized in that Xes Gly, Yes Pro and Z is De; Xes Ala. Yes Pro and Z esDe; Xes Arg. And is Pro and Z esDr, Xes Alp, Yes? and Z is De; Xes Tr, Yes Pro and Z is De; Xas Ser, Yes Pro and Z esPhe; or Xes Gly, Yes Pro and Z is Pro; to be used as an immunoregulatory agent. 16. The peptide according to any of claims 13, 14 and 15, characterized in that A is H, a protecting group selected from Ac, Fmoc, Bpoc, Trt, Alloc and Boc, an amino acid either in the L or D form selected from Phe, Leu, Met, Ser, Lys or Tyr with or without the functionality of the protected side chain and / or the N-terminal protective group selected from Ac, Fmoc, Bpoc, Trt, Alloc and Boc or an amino acid sequence with or no functionalities with either Phe, Leu, Met, Ser, Lys or Tyr in the C-terminal side of the sequence, with or without the functionalities of the protected side chain and / or the selected N-terminal protective group of Ac, Fmoc , Bpoc, Trt, Alloc and Boc; and B is OH, NH 2, a protecting group selected from C 1 Cg alkyl, allyl, adamantyl, benzyl and t-butyl, an amino acid either in the L or D form selected from Leu, Lys or Arg with or without the functionality of the protected chain later and ending with a C-terminal amide, a free carboxyl or a protecting group selected from C - ^ - Cg alkyl, allyl, adamantyl, benzyl and t-butyl or an amino acid sequence with or without the functionalities either Leu, Lys or Arg at the N-terminal side of the sequence, with or without the functionalities of the protected side chain and ending with a C-terminal amide, a free carboxyl or a protective group selected from C ^ alkyl. -C, allyl adamantine, benzyl and t-butyl, to be used as an immunoregulatory agent. 17. The use of a peptide comprising 4-15 amino acids in accordance with formula (I) A-X-Y-Cys-Z-B (I) wherein X was selected from Gly, Ala, He, Asp, Thr, Ser, Arg or Trp; And it was selected from Pro, Pee or Lie; Z was selected from He, Phe, Pro, Ala, Tyr or Gly; A is H, a protective group, an amino acid either in the L or D form with or without the functionality of the protected side chain and / or the N-terminal protection or a sequence, of amino acids with or without functionalities of the chain .teral protected and / or N-terminal protection; B is OH, NH2, a protective group, an amino acid. either in the L or D form with or without the functionality of the protected side chain and ending with an amide in the C-terminus, a free carboxyl or a protecting group or an amino acid sequence with or without the functionalities of the chain protected and terminating with a C-terminal amide, a free carboxyl or a protecting group; with the proviso that the following sequences are excluded from the formula (I): Tyr-De.Pro-Cy? -Phe-Pro-Se ^ Sa-l ^ -L ^ OE IDENT. N0: 36). Tyr-De.Pro ^ », Í ^ Pro-Scr-S € r-eo-ys-Ar? -LeD.pe (SE IDENTIFICATION N0: 37). TTff.p? T > J »ro-Thr-Pro-Cy? -Pro-Ser (sec DEIDENT ?: 39), the length of A and B may vary, while the criteria relate to the length and possible amino acids are met; and wherein the peptides of the formula (I) containing various cysteine residues may both exist in an oxidized fortra and in a reduced form, wherein the oxidized faith may contain intramolecular disulfide bonds resulting in oxidized monomers or intramolecular disulfides resulting in both domains from the front to the front and from the front to the back of the peptides of the formula (I) as well as their pharmaceutically acceptable salts of a peptide of the formula (I); for the manufacture of a medicine with immunoregulatory effect. 18. The use of a peptide according to claim 17, wherein the following sequence is excluded from formula (I): Asp-Pro-Cys-He-He, for the manufacture of a medicament with immunoregulatory effect. 19. The use of a peptide according to any of claims 17 and 18, wherein Xes Gly, Yes pro and ZesDe; XesGly. esPro and ZesGly, Xes Ala, Y is Pro and ZesAlt; Xes De, YesPro and Z «* Tyr. Xes Ala, Yes Pro and Zes De; Xes Arg, Yes Pro and Ze De; Xes De, YesPro and ZesDe: Xes A », YesPro and ZesDe; X is Tr, Y is Pro and Z is Oe; X esTrp, Yes Pro and Z is Gly: Xes Gly, Yes De and Zes De; X is Gly, Y is Pee and Z is De; X isThr, YesPro and Z is Tyr. Xes Thr, Yes Pee and ZesPhe; Xes Ala, Yes Pro and Zes he; Xes Ser, YesPro and Zes he: XesGly, And it's Pro and Zes Pro; or XesGly, YesPro and ZesTyr, for the manufacture of a medicine with immunoregulatory effect. 20. The use of a peptide according to any of claims 17, 18 and 19, wherein Xes Gly, YesPro and Z is De; Xes Ale, YesPro and Z is De Xes Axg, YesPro and Z is De; Xes Ajp, YesPro and Z is De esTrp, YesPro and ZesDe; XesSer, YesPTO and ZesPhe or XesGly, esPro and Zes Pro; for the manufacture of a medicine with immunoregulatory effect. 21. The use of a peptide according to any of claims 17, 18, 19 and 20, wherein A is H, a protecting group selected from Ac, Fmoc, Bpoc, Trt, Alloc and Boc, an amino acid either in the L or D form selected from Phe, Leu, Met, Ser, Lys or Tyr with or without the functionality of the protected side chain and / or < = * • N-terminal protective group selected from Ac, Fmoc, Bpoc, Trt, Alloc and Boc or an amino acid sequence with or without functionalities with either Phe, Leu, Met, Ser, Lys or Tyr at the lateral C-terminus of the sequence, with or without the functionalities of the protected side chain and / or the selected N-terminal protecting group of c, Fmoc, Bpoc, Trt, Alloc and Boc; and B is OH, NH2, a protecting group selected from C-j_-Cg alkyl, allyl, adamantyl, benzyl and t-butyl, an amino acid either in the L or D form selected from Leu, Lys or Arg with or without the functionality of the protected side chain and ending with a C-terminal amide, a free carboxyl or a protecting group selected from C-, C6, allyl, adamantyl, benzyl and t-butyl alkyl or an amino acid sequence with or without the functionalities either Leu, Lys or Arg at the N-terminal side of the sequence, with or without the functionalities of the protected side chain and terminating.-with a C-terminal amide, a free carboxyl or a protective group selected from C 1 -C 6 allyl, adamantyl, benzyl and t-butyl alkyl, for the manufacture of a medicament with immunoregulatory effect. 22. The use of a peptide comprising 4-15 amino acids in accordance with formula (I) A - X - Y - Cys - Z - B (I) wherein X was selected from Gly, Ala, He, Asp, Thr, Ser, Arg or Trp; And it was selected from Pro, Pee or He; Z was selected from He, Phe, Pro, Ala, Tyr or Gly; A is H, a protecting group, an amino acid either in the L or D form with or without the functionality of the protected side chain and / or the N-terminal protection or an amino acid sequence with or without functionalities of the protected side chain and / or N-terminal protection; B is OH, NH2, a protecting group, an amino acid either in the L or D form with or without the functionality of the protected side chain and ending with an amide at the C-terminus, a free carboxyl or a protecting group or a sequence of amino acids with or without the? -function of the side chain protected and terminating with a C-terminal, a free carboxyl or a protecting group; with the proviso that the following sequences are excluded from the formula (I): Leo- »? ^ $ ^ Y-Pro ^ Phe La (ID SECTION N0 J4), Leo ^ AJi-Gr ^ Pro ^ Phß. e (SEC.DEIDEMT.K0: 3 Tyr-De »ro Cy? lM> g * Se $« f4 e? ^^ DE IDENT NO-36), Tyr.De-Pro-Cys-Pt ^ Pto-S -S ^ Le? - yvArg.Lea-D «(ID SECTION NO: 37), Ser 31y-Pr CyvPp > -Ly? -Ayf-GIy ^ the-Pro-Ser (3 £ C IDENT N0: 3I and Thr-Pro-Pr¡> -Tl * -Pro «Cys-Pro-Ser (SEC. : 39), and with the proviso that when X is Arg or Ala and Y is He, Z is not Phe, Pro, He or Gly; the length of A and B may vary, while the criteria are related to the length and possible amino acids are met; and wherein the peptides of the formula (I) containing various cysteine residues can both exist in an oxidized form and in a reduced form, wherein the oxidized form can contain intramolecular disulfide bonds resulting in oxidized monomers or intramolecular disulfides resulting in both dimen- sions from the front to the bottom side and from the front to the back of the peptides of the formula (I) as well as their pharmaceutically acceptable salts of a peptide of the formula (I); for the manufacture of a medicament for oral administration. 23. The use of a peptide according to claim 22, wherein XesGly. And »* Pro and ZesDe; XesGly, Yes Pro and ZesGhr, Xes Alt, Y is Pro and Zes Alt; Xes DcYesPro and ZesTyr, XesA, YesPro and ZesDe; XesA? G.YesPro and ZesDe: Xes De, Yes Pro and ZesDe; XesAap, Yesft? And ZesDe; XesTrp, YesPro and ZesDe; XesT? P, YesPro and ZesGly; XesGry.YesDe and ZesDe; XesGly, Yes Pee and Z esQe; X esThr, Yes Pío and Z esTyr; XesThr, Yes Pee and Zes Phe; XesAlt, YesPro and Zes Phe: XesSer, Y »s Pro and Z is Phe; XesGly, Yes Pro and Zes Pro; or XesGly, Yes ft and ZesTyr, for the manufacture of a medication for administration. oral. 24. The use of a peptide according to claim 22, wherein XesGly. YesPro and Zes De; XesAlt, YesPro and ZesDe; XesArg, Yes Pro and ZesDe; Xes Asp, YesPro and Z is De; Xes Tro, Y esPro and ZesDe; Xes Ser. YesPro and ZesPhe or Xes Gly, YesPro and ZesPro; for the manufacture of a medicament for oral administration. 25. The use of a peptide according to any of claims 22, 23 and 24, wherein A is H, a protective group selected from Ac, Fmoc, Bpoc, Trt, Alloc and Boc, an amino acid either in the L form or D selected from Phe, Leu, Met, Ser, Lys or Tyr with or without the functionality of the protected side chain and / or the N-terminal protective group selected from Ac, Fmoc, Bpoc, Trt, Alloc and Boc or a sequence of amino acids with or without functionalities with either Phe, Leu, Met, Ser, Lys or Tyr in the C-terminal side of the sequence, with or without the functionalities of the protected side chain and / or the selected N-terminal protecting group of Ac, Fmoc, Bpoc, Trt, Alloc and Boc; and B is OH, NH2, a protecting group selected from alkyl ie C ^ -C, allyl, adamantyl, benzyl and t-butyl, an amino acid either in the L or D form selected from Leu, Lys or Arg with or without the functionality of the protected side chain and terminating with a C-terminal amide, a free carboxyl or a protecting group selected from C-, C8-alkyl, allyl, adamantyl, benzyl and t-butyl or an amino acid sequence with or without the functionalities either Leu, Lys or Arg at the N-terminal side of the sequence, with or without the functionalities of the protected side chain and terminating with a C-terminal amide, a free carboxyl or a protective group selected from C-terminal C6'-allyl adamantyl, benzyl and t-butyl, for the manufacture of a medicament for oral administration. 26. A method for immunoregulation, whereby an effective amount of a peptide characterized in that it comprises 4-15 amino acids in accordance with formula (I) A - X Y - Cys B (I) wherein X was selected from Gly, Ala, He, Asp, Thr, Ser, Arg or Trp; And it was selected from Pro, Pee or Lie; Z was selected from He, Phe, Pro, Ala, Tyr or Gly; A is H, a protecting group, an amino acid either in the L or D form with or without the functionality of the protected side chain and / or the N-terminal protection or an amino acid sequence with or without functionalities of the protected side chain and / or N-terminal protection; B is OH, NH2, a protecting group, an amino acid either in the L or D form with or without the functionality of the protected side chain and ending with an amide at the C-terminal, a free carboxyl or a protecting group or a sequence of amino acids with or without the protected side chain functionalides and ending with a C-terminal aptaa, a free carboxyl or a protecting group; with the proviso that the following sequences are excluded from the formula (I): u-Cys-A.a ^ ly-iro-Cys-Phe-Leu (SK DE iDENT NO: 33). Tyr-lle-Pp > ^ Phe'Pro-Ser-Ser-eu-L ^ Arg 'a-ne (SEQ ID NO: 37), Ser ny-Pro ^ Pro-L? -A? ^ Iy ^^ and Trr-Prc-Pro-Thr.Pro-Cys.Pro-Ser (SEQ.ID.NO.:39 >, the length of A and B may vary, while the criteria are related to the length and possible amino acids are met; and wherein the peptides of the formula (I) containing various cysteine residues may both exist in an oxidized form and in a reduced form, wherein the oxidized form may contain intramolecular disulfide bonds that result in oxidized monomers or intramolecular disulfides that they result in both dimers from the front to the front and from the front to the back of the peptides of the formula (I) as well as their pharmaceutically acceptable salts of a peptide of the formula (I); it is administered to a host that needs immunoregulation. 27. The method for immunoregulation, whereby an effective amount of a peptide according to claim 26, characterized in that the following sequence is excluded from formula (I): Asp-Pro-Cys-Ile-Ile, it is administered to a host that needs immunoregulation. 28. The method for immunoregulation, whereby an effective amount of a peptide according to any of claims 26 and 27, characterized in that XesGly, Yes Pro and Z esDe; XesCHy, Yes Pro and Z is Gry; Xes Ala, Yes Pro and Z ßsAla; XesDe, Yes Pro and Z isTyp Xes Ala, Yes Pro and Z is De; XesArg, YesPro and Z esDe; XesDe, YesPro and Z is De; XesAsp, YesPro and Z is De; XesTrp, YesPro and Z esDe; XesTrp, YesPro and Z is Gly. XesGly. Yes From and Z esDe; XesGly. YesPec and Z esOe; XesThr, Yes Pro and Z sTyr, XesThr, esPe and Z esPhe; Xes Ata, YesPTO and Z esPhc XesSer, YesPro and Z is Phß; XesGly, Yes Pro and Z «Pro; or XesGly, esPro and Z isTy it is administered to a host that needs immunoregulation. 29. The method for immunoregulation, whereby an effective amount of a peptide according to any of claims 26, 27 and 28, characterized in that XesGly, YesPro and ZesDe; XesAta, YesPro and ZesDe; XesArg, YesPro and ZesDß; XesAJO, YesPro and ZesDß; XesTrp, YesProyZ «* From; XesSer.YesProyZ is Phe; or XesGly, Y is Proy Z is Pro; it is administered to a host that needs immunoregulation. 30. The method for immunoregulation, whereby an effective amount of a peptide according to any of claims 26, 27, 28 and 2 characterized in that A is H, a protecting group selected from Ac, Fmoc, Bpoc, Trt, Alloc and Boc, an amino acid either in the L or D form selected from Phe, Leu, Met, Ser, Lys or Tyr with or without the functionality of the protected side chain and / or the N-terminal protective group selected from Ac, Fmoc, Bpoc, Trt, Alloc and Boc or an amino acid sequence with or without functionalities with either Phe, Leu, Met, Ser, Lys or Tyr at the C-terminal side of the sequence, with or without the functionalities of the protected side chain and / or the N-terminal protective group selected from Ac, Fmoc, Bpoc, Trt, Alloc and Boc; and B is OH, NH 2, a protecting group selected from C 1 -Cg alkyl, allyl, adamantyl, benzyl and t-butyl, an amino acid either in the L or D form selected from Leu, Lys or Arg with or without the functionality of the protected side chain and terminating with a C-terminal amide, a free carboxyl or a protecting group selected from C - ^ - Cj alkyl. allyl, adamantyl, benzyl and t-butyl or an amino acid sequence with or without the functionalities either Leu, Lys or Arg at the N-terminal side of the sequence, with or without the functionalities of the protected side chain and ending with A C-terminal amide, a free carboxyl or a protecting group selected from C 1 -C 6 allyl, adamantyl, benzyl and t-butyl alkyl is administered to a host in need of immunoregulation. 31. A homodimer of a peptide characterized in that it comprises 4-15 amino acids in accordance with formula (II), (III) or (IV) A-X-Y-Cys- • Z- B (ni) A-X-Y-Cyf-Z-B , X-Y; jqyf-Z-B (TV) X-Y ^ y? -Z-B; wherein X was selected from Gly, Ala, He, Asp, Thr, Sei, Arg or Trp; And it was selected from Pro, Pee or Lie; Z was selected from He, Phe, Pro, Ala, Tyr or Gly; A is H, a protective group, an amino acid either in the form. L or D with or without the functionality of the protected side chain and / or the N-terminal protection or an amino acid sequence with or without functionalities of the protected side chain and / or the N-terminal protection; B is OH, NH2, a protecting group, an amino acid either in the L or D form with or without the functionality of the protected side chain and ending with an amide at the C-terminus, a free carboxyl or a protecting group or a sequence of amino acids with or without the protected side chain functionalities and ending with a C-terminal amide, a free carboxyl or a protecting group; the length of A and B may vary, while the criteria are related to the length and possible amino acids are met; and also their pharmaceutically acceptable salts of the peptides of the formula (II), (III) or (IV); and with the proviso that the following homodimers are excluded: H lly-D «- < j »-Pro-Leo-Cys (AOT) -Met < XOH H-Gly-D? T-C7 »-Pro- or ^^ Ar? Met < X) -OH wherein Acm is acetamidomethyl and (X) is oxygen without oxygen. 32. The homodimer according to claim 31, characterized by Xes Gly, Y is Pro and Zes De; Xes Gly, Yes RQ and ZesGly; XesAla, YesPro and Zes Ala; XesDe, YesPro and ZesTyr, Xes Ala, YesPro and Z eslíe; X is Arg, Yes Pro and ZesDe; XesDe, YesPro and ZesDe; XesAsp, YesPro and ZesDe; XesTrp, YesPro and ZesDe; XesTrp, Yes Pro and ZesGly; Xes01y, YesDe and Ze De; XesGly, And it's Pee and ZesDe; XesThr. YesPro and Zes Tyr, XesThr, YesPec and ZesPhe; Xes Ala, YesPro and ZesPhe; Xes Ser, YesPro and Z is Phe; X is Gly, Yes Pro and Z is Pro; or X is Giy. Yes Pro and Z is Tyr. 33. The homodimer according to claim 31, characterized in that X «« Oljr.YMFse and 2MBe; X ««? Ja, V «« P? O and ZM0 «: X« s? Sp. YMPN and 2 «* Oe¡ X..Trp, Y.« Pro and ZnDa; XßsSec. And «sPro and Z« «Phe; or X« sOIy. V «« Pro and Z «* P? . 34. The homodimer according to any of claims 31, 32 and 33, characterized in that A is H, a protective group selected from Ac, Fmoc, Bpoc, Trt, Alloc and Boc, an amino acid either in the L or D form selected from Phe, Leu, Met, Ser, Lys or Tyr with or without the functionality of the protected side chain and / or the N-terminal protective group selected from Ac, Fmoc, Bpoc, Trt, Alloc and Boc or an amino acid sequence with or no functionalities with either Phe, Leu, Met, Ser, Lys or Tyr in the C-terminal side of the sequence, with or without the functionalities of the protected side chain and / or the selected N-terminal protective group of Ac, Fmoc , Bpoc, Trt, Alloc and Boc; and B is OH, NH2, a protecting group selected from C] _ C, allyl, adamantyl, benzyl and t-butyl alkyl, an amino acid either in the L or D form selected from Leu, Lys or Arg with or without the functionality of the side chain "protected and ending with a C-terminal amide, a carboxyl-free on protecting group selected from C - ^ - Cg alkyl, allyl, adamantyl, benzyl and t-butyl or an amino acid sequence with or without the functionalities either Leu, Lys or Arg at the N-terminal side of the sequence, with or without the functionalities of the protected side chain and terminating with a C-terminal amide, a free carboxyl or a protective group selected from alkyl of C ^ -8, allyl, adamantyl, benzyl and t-butyl. 35. The homodimer according to claim 31, characterized in that it is H rly-PpM s-De-OH H-Gly-Pp > -Cy8-De-OH (homodimer of SECTION DE DENT. NO: 1); Fnw- and-Pro-Cys-De-OH Fpvx-Gty-Pro-Cvs-De-OH (homodimer of SECTION SEMT NO: 1): (HORN OF THE IDBfT S C C NO: 2> H-Ala-Prí-Cys-Ala-OH H-Ala-Pra-Cy-Ala-OH (homodimer of b SECTION OF OBiT. NO; 3 ): H-De-Pre-Cyi-Tyr-OH H-Oe-Pro-yt-Tyr-OH (homodier of S £ CD £ IOEMT.N0.); H-Tro rc? Cys-Gy-OH HT? p »ro-Cy» -Gly-OH (homodimer ebSEC.DEI] Bir.W) E32: (homodimer (JebSf &DE COK IttS); H ^ H-I ^ ^ De-Leo-Aa-NHi H Hy »KHCy? -ae-Leo-Aß- Hj (homol rodelaSE.Kt) fflT.Wl«); (homoduct of SECDEIDBGT.N0: 7) Í H-Leo-u-Plie-Gly-Pro-Cys-De-OH H-Lai-biu-Ptie-Gly-Pro-Cya-De-OH (homodimer of b SEC DEIOET.NO: 8): H-Leu-Un? -rpe ^ ly-Pro-Cy «-pe-OH H- u-Lm? -D-Ptw Uy-Pro-Cys-pe-OH (homodrier of b SECTION DE ID. NO: 8 ); H-eo ^ Leo-PIt-s-Ala-Pro-Cys-De-GH H-Lea-Lw-Phe-Ala-Pro-Cys-ue-OH (omodimer of the SEC, DE DENT. NO: 9); H-Leor-Lai-Pta-Arg-Pro-Cye-De-GH H-1 ^ -b-p ^ ^ Arg-Pro-Cys-rje-OH (homodimer of b SEQ ID NO: 10); H-L-eo-L ^ -Phe-rJe-Pro-Cyß-De-OH H-Leß- "-Phe-De-Prc-de-OH (homodimer of b SEQ ID NO: 11); (homod ?? modebSE 0EIDEHT.N0: 12); (homodfcmro de b SEC.De10ENT.NO:13); H- u- or-Phe-Gly-De-Cys-Ile-OH H-Leu-Phe rly-De-Cys-De-OH (homodimer of b 5EC.DE! DEHT.N0:! 4); l3fc 33 > 16); : 17): H-Leo-e * ß-Tyr-S «r-Pro < tPhe-OH H-Leo- ^ Tyr-S ^ Pro ^ yt-Pe ^ H (homodfcmro ae b SEC. DEDENT.NO: II); (homodr rodebSECDED? p.NO.19); H-Phe-Le * a-Phß-Gly-Pro-Cys.ae-OH H-Plie-t ^ -Phe-Gly-Pro-Cya-De-OH (omodlimer of b SECTION OF CENT NO: 20); H-Leu-Pl »e? T-Pro 8-De-eu-NH2 H-U ?? -Phe-01y-Pre ya-De? I-NH2 (homodimer of ta SEC DE CENT. NO: 21); (homodlmerodebSECDEDB «T.Nft22); H-Leß-Leß-Phß ^ ly-l o- ^ De-Leß-OH H- ol ^ -Phß-Oyy-Pio- ^ »- De-Lett ^ 3H (homodimest of b SECTION ID N023): H - u-Leu-Phe-Gry-I e- ^ De-Leo- H2 H-Lea-Leo-PhtGry -? ^ o ^ Oe- u-Nrh (homodimer of SECDEIQENT.NOOe); H-Leu-Lett-Phe-Gly-P? ^ FytD Leß-OA ^ H-Leo-L ^ Phe-Gly-Prc- ^ De-Leo »Allyl (hornodtnerod USEC.DEDEMT.W'23); H-Leß-Lßtt-Pl? E-siy-Pto ^ De? ß-A? A.NH2 H-Leo- »P1? ß-ay-Pw- ^ De-Lett-Asn.NH2 (l8nodimero of b SEC OE I0EST, NO: 25); H- or ?? ß-P1? E-Gí - »- ^ Dß.l? -Asa-Ar ^ H-Lßu-Le? O-I ^ -a- ro-C ^ Dß-1-ea-At». Arg-OH (homodimer of the SEC DE IDEHT, No. 26); H - «» Le * -Bfc > C | y * t ^ H-Pl »e-Le * Phß-siy-Pre- < ! ^ De- e «-Asfr (homodimest of b SEC OECEJ (T.N &27); (homodimer of b SEC DÉ CENT NO; »* (homodimer of SECDE IOEN, NO: 29); (homodimer of SEO ID N0: 29); or H-Pl ^ t- or-Gly-Pro-Cys-Pro-OH H-Phe ^^ Leo-Gly-ro ^? -Pro-OH (homodimer of b SEC.DE ICEHT .NO: 30 36. The homodimer according to claim 31, characterized in that it is H-Gly-Pro-Cys-ne-OH H-siy-Pro-Cys-Dβ-H (homodimer of SE € OE lOENT NO: 1); (Homodimer of ID SECTION T. NO: i); H-Le »- tt-Tyr-Ser-Ptc ^ -Phe-CW H-I ß-L« ^ Tyr-Ser-Pto-Cy * -Pbe-OH (homodlymer of SEC.OE IOENT.NO: II); (homodl ery of the SECTION OF lOENT NO: 2tl (front to front of Homodimer of SEC. DE CENT. * 30); or (part delantare to rear part of homodfmero of SEC. DE DENT. MO: 30V 37. The homodimer according to claim 31, characterized in that it is H- u-L "hPb * -Gly-Prc-Cys-De" OH H-l ^ 4 ^ Phe-Gly-Pro-Cys-De-OH (homodimer of SEQ ID NO::); H-1 ^ -LefrTyr-Ser-Pto-Cys-Phe-OH H-La.-LetrTyr-Sef-Pro-Cys-Phe-OH (homodimer of SEQ ID NO: 18); (front to front of homodfomer of SECTION ID NO: 30); or (front to rear of homologous of SEQ ID NO: 30). 38. A peptide characterized in that it comprises 4-15 amino acids in accordance with formula (I) A - X - Y - Cys - Z - B (I), in which Xas Gly, Vs Piro and ZesDe; XesCfly, Yes Pro and Z is Qy *. XesAla, resPro and Z isAlc X eslíe, Yes Pto and Z isTyR Xes Ala. Yes Pro and ZesDes X sArf, lTesr? and Z esDe; XesDe, YßsPro and ZesDe; Xes Aap, Yes Pro and Z «De Xes Tro, YesPro and Z esDc; X is Trp, Yes Pro and Z is Gly; XesGly, Yes De and ZesDe; XesGly, Yes Pee and ZesDe; XesThr, YesPro and ZesTyr, XesThr, Y espßc and ZesPhe; Xes Ala, Yes h and ZesPhe; XesSer, YesPro and ZesPhe; XesGly, Yes Fro and Zes Pro; or XesGhjr, YesPro and ZesTyr, A is H, a protective group, an amino acid either the L or D form with or without the functionality of the protected side chain and / or the N-terminal protection or an amino acid sequence with or without functionalities of the protected side chain and / or N-terminal protection; B is OH, NH2, a protecting group, an amino acid either in the L or D form with or without the functionality of the protected side chain and ending with an amide at the C-terminal, a free carboxyl or a protecting group or a sequence of amino acids with or without the protected side chain functionalities and ending with a C-terminal amide, a free carboxyl or a protecting group; with the proviso that the following sequences are excluded from the formula (I): Asp-Pro-Cys-Ile-Ile C ^? - ay < íry-De-Cy De ^ AltrArg, Gty-Pr- ^ T ^ Rw ^ JliAtJ ^ the length of A and B may vary, while the criteria are related to the length and possible amino acids are met; and also their pharmaceutically acceptable salts. 39. The peptide according to the claim 38, characterized in that XesGly, YesPro and Zes De; XesAla ,, YesPro ZesDe; XesArg, YesPro and ZesDe; XesAsp, Yes Pío and ZesDe; XesT, YesPro and ZesDe; X isSer. And it's Pro and ZesPhe, or XesGly YesPro and ZesPio. 40. The peptide according to any of claims 38 and 39, characterized in that A is H, a protective group selected from Ac, Fmoc, Bpoc, T_;, Alloc and Boc, an amino acid either in the "L or D" form selected of Phe, Leu, Met, Ser, Lys or Tyr with or without the functionality of the protected side chain and / c the N-terminal protective group selected from Ac, Fmoc, Bp Trt, Alloc and Boc or an amino acid sequence with or no functionalities with either Phe, Leu, Met, Ser, Lys or Tyr in the C-terminal side of the sequence, with or without the functionalities of the protected side chain and / or the selected N-terminal protective group of Ac, Fmoc , Bpoc, Trt, Alloc and Boc, and B is OH, NH2 a protecting group selected from C1-C8 alkyl, allyl, adamantyl, benzyl and t-butyl, an amino acid either in the L or D form selected from Leu, Lys or Arg with or without the functionality of the protected side chain and ending with a C-terminal amide, a free carboxyl or a protected group r selected from C, -Ci, allyl, adamantyl, benzyl and t-butyl alkyl or an amino acid sequence with or without the functionalities either Leu, Lys or Arg at the N-terminal side of the sequence, with or without the functionalities of the protected side chain and ending with a C-terminal amide, a free carboxyl or a protecting group selected from C 1 -C 6 allyl adamantyl, benzyl and t-butyl alkyl. 41. The peptide according to the claim 38, characterized because it is 1 H- e ^ H? ß-Oly-Pro-Cya-De-Lett-NHa (SEC.DEDENT.N0: 2l); H-Ghj-1, ys-Cly-Pro-Cya-Tyr-Arg-OH (SEQ ID NO: 22); H- u- u-Phe-Gly-Pro-Cys-De-Leu-OH (SEQ.ID.NO:23); H- u- or-Pe-G ^ Pro-Cy? -De-L ^ .W2 (SECDEIDENT.N0: 24) í H-Lealea 1 »> Gl ^ Pl (? < ^ lleLeih ^ (SEC OE lOENT NO: 23); H-Leo -e * Tkay «Pre-Cys-De-eu-AsihNH2 (SEC DE IDENTIFIER NO: 25); H-Leß * ß-Phe-Gry-Pro-Cy * -lle.Le * (DENSE SECTION NO: 26, HP Leo-Phe-Gry-Pro-Cyj-De-l ^ As ^ (SEC OE IDENT. 27); H-Leo - .. ju-Phc-Qly-Pro-Cyt-0c. «A-A ^ (SE 0EIDENT.NO:2t)? H-Pla L.a-Phe-Gly-Pro-Cyf-D Le (3EC DE IOIEMT, NO; 29); FpHX-Pl? E-Leo-Pl > e-Qy-I ¥ o -V »-De-Leß-A» - (SEQ.ID.NO: 29) or H-Pl? eO ^ f-LeB-Gly-Pro-Cys-Pro-OH ( SECTION OF DBIT, NO: 30). 42. The compliance peptide of claim 8, characterized in that it is H-Gly-Pro-Cyi-Dβ-OH (SEC DE DENT. NO: 1); H-Al ».Pro-C» .Ala-OH (SE DEDENT.N0: 3); -Pb * < lr-Pi0-Cy% > ? + OH (SECTION DE DENT. N0: 5); H-Leo-Leih? ß-Al * ^ 0-Cyf-D ^ 0H (SECTION OF DENT NO: 9) H-Lai-Leo-Pfcβ-? Jp-Pro-Cyt-De-OH (SEC. DE IDENT NO: 12); H- or-Le * «« > Gly-De ^ De DH (SEC, DE IDENT NO: 1)? H-Le * * Phe431y-Pe? > Cy (SEQ ID NO: 15); H- o-Ler > Tyr-Sef-Pre ^ P! A > OH (SEQ ID NO: II); H44 »Le» -fhfr Ily ^^ (SEC DE DENT. N0: 23); H-P1a > Cyt-ea-Gry4 > ro-Cyt-Pro-0H (SEQ ID NO: 30); or 43. A pharmaceutical preparation characterized in that it contains a homodimer according to claim 31 as an active ingredient, together with a pharmaceutically acceptable carrier. Four . The process for the preparation of a homodimer in accordance with claim 31, characterized in that the amino acids are sequentially linked in solid phase using an automatic synthesizer or the amino acids are joined in stages in a phase in solution using the appropriately derivatized amino acids. 45. A pharmaceutical preparation characterized in that it contains a peptide according to claim 38 as an active ingredient, together with a pharmaceutically acceptable carrier. 46. The process for the preparation of a peptide according to claim 38, characterized by? the amino acids are sequentially linked in solid phase using an automatic synthesizer or the amino acids are joined in stages in a phase in solution using appropriately derivatized amino acids.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9403526A SE9403526D0 (en) | 1994-10-14 | 1994-10-14 | New Peptides |
| SE9403526.8 | 1994-10-14 | ||
| PCT/SE1995/001151 WO1996011943A1 (en) | 1994-10-14 | 1995-10-06 | New peptides with immunomodulatory effects |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MXPA97002666A true MXPA97002666A (en) | 1997-06-01 |
| MX9702666A MX9702666A (en) | 1997-06-28 |
Family
ID=20395628
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| MX9702666A MX9702666A (en) | 1994-10-14 | 1995-10-06 | New peptides with immunomodulatory effects. |
Country Status (20)
| Country | Link |
|---|---|
| US (2) | US6103697A (en) |
| EP (1) | EP0783519A1 (en) |
| JP (1) | JPH10507448A (en) |
| AU (1) | AU705364B2 (en) |
| BR (1) | BR9509345A (en) |
| CA (1) | CA2201479A1 (en) |
| CZ (1) | CZ111997A3 (en) |
| EE (1) | EE9700087A (en) |
| FI (1) | FI971499A (en) |
| HU (1) | HUT77118A (en) |
| IL (1) | IL115509A0 (en) |
| IS (1) | IS4459A (en) |
| MX (1) | MX9702666A (en) |
| NO (1) | NO971625L (en) |
| PL (1) | PL319631A1 (en) |
| SE (1) | SE9403526D0 (en) |
| SK (1) | SK46797A3 (en) |
| TR (1) | TR199501255A2 (en) |
| WO (1) | WO1996011943A1 (en) |
| ZA (1) | ZA958140B (en) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE9403526D0 (en) | 1994-10-14 | 1994-10-14 | Astra Ab | New Peptides |
| SE9501067D0 (en) | 1995-03-24 | 1995-03-24 | Astra Ab | New peptides |
| AU2417597A (en) * | 1996-04-12 | 1997-11-07 | Astra Aktiebolag | Cysteine-containing or methioine-containing peptides with immunomodulatory ef fects |
| AU3453897A (en) * | 1996-07-08 | 1998-02-02 | Rhone-Poulenc Rorer Limited | Medicinal cyclosporin-a aerosol solution formulation |
| SE9603467D0 (en) * | 1996-09-23 | 1996-09-23 | Astra Ab | New compounds |
| SE9603465D0 (en) * | 1996-09-23 | 1996-09-23 | Astra Ab | New compounds |
| SE9603461D0 (en) * | 1996-09-23 | 1996-09-23 | Astra Ab | New compounds |
| SE9603463D0 (en) * | 1996-09-23 | 1996-09-23 | Astra Ab | New compounds |
| SE9603468D0 (en) * | 1996-09-23 | 1996-09-23 | Astra Ab | New compounds |
| SE9603466D0 (en) * | 1996-09-23 | 1996-09-23 | Astra Ab | New compounds |
| SE9603462D0 (en) * | 1996-09-23 | 1996-09-23 | Astra Ab | New compounds |
| AU9655698A (en) * | 1997-10-10 | 1999-05-03 | Astra Aktiebolag | Synthetic genes with immunomodulatory effects |
| EP1083872A1 (en) * | 1998-06-03 | 2001-03-21 | GPI NIL Holdings, Inc. | Pipecolic acid derivative hair growth compositions and uses |
| RU2144374C1 (en) * | 1998-11-23 | 2000-01-20 | Закрытое акционерное общество "ВАМ" | Method of preparing of oxidized glutathione-cis- diaminodichloroplatinum complex and pharmaceutical compositions based on this complex for controlling metabolism, proliferation, and differentiation, and mechanisms of apoptosis of normal and transformated cells |
| JP4711520B2 (en) * | 2000-03-21 | 2011-06-29 | 日本ケミカルリサーチ株式会社 | Bioactive peptide-containing powder |
| US7265208B2 (en) * | 2001-05-01 | 2007-09-04 | The Regents Of The University Of California | Fusion molecules and treatment of IgE-mediated allergic diseases |
| US8080560B2 (en) | 2004-12-17 | 2011-12-20 | 3M Innovative Properties Company | Immune response modifier formulations containing oleic acid and methods |
| PL1948782T3 (en) | 2005-04-25 | 2013-01-31 | Cadila Pharmaceuticals Ltd | Vaccine adjuvants |
| KR101363455B1 (en) * | 2011-09-09 | 2014-02-21 | (주)케어젠 | Peptides Inhibiting the Activity of Matrix Metalloproteases and Use Thereof |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4585755A (en) * | 1985-04-29 | 1986-04-29 | Merck & Co., Inc. | Cyclic and bridged cyclic somatostatin analogs useful as local anti-inflammatory agents |
| US4822606A (en) * | 1986-04-07 | 1989-04-18 | Duke University | Immunosuppressive synthetic peptides and analogs thereof based on retroviral envelope sequences |
| JPH01501939A (en) | 1987-01-28 | 1989-07-06 | オーソ・フアーマシユーチカル・コーポレーシヨン | Immunosuppressive peptides and usage |
| FR2622700B1 (en) | 1987-10-30 | 1993-08-13 | Aderegem | PROTEIN AND ITS FRAGMENTS REPRESENTING THE SPECIFIC EXPRESSION OF THE PS2 GENE OF BREAST CANCERS, ANTIBODIES OBTAINED FROM SAID PROTEIN AND / OR FRAGMENTS THEREOF, THEIR APPLICATIONS FOR THE DETECTION AND DIAGNOSIS OF BREAST CANCERS |
| WO1989010935A1 (en) * | 1988-05-09 | 1989-11-16 | Abbott Laboratories | Atrial peptide derivatives |
| US5223485A (en) * | 1989-01-31 | 1993-06-29 | Abbott Laboratories | Anaphylatoxin-receptor ligands |
| WO1992004445A1 (en) | 1990-09-11 | 1992-03-19 | The Western Australian Research Institute For Child Health Ltd. | Cloning and sequencing of allergens of dermatophagoides (house dust mite) |
| JP2596466B2 (en) | 1990-03-03 | 1997-04-02 | アサヒビール株式会社 | DNA having transfer information of major allergen of mite and method for producing the allergen |
| AU2296792A (en) * | 1991-06-28 | 1993-01-25 | Corvas International, Inc. | Novel inhibitors of platelet aggregation |
| JP2657861B2 (en) | 1991-09-17 | 1997-09-30 | アサヒビール株式会社 | Method for producing major mite allergen |
| KR100260342B1 (en) | 1991-10-16 | 2000-07-01 | 스타세이 엘. 첸링 | T cell epitopes of the major allergens from dermatophagoides |
| JP3149033B2 (en) | 1991-10-30 | 2001-03-26 | アサヒビール株式会社 | Peptides in the mite major allergen Der f II |
| ATE466869T1 (en) | 1993-03-05 | 2010-05-15 | Epimmune Inc | METHOD FOR PRODUCING IMMUNOGENIC HLA-A2.1-BINDING PEPTIDES |
| IL106214A (en) * | 1993-07-01 | 1998-12-06 | Yeda Res & Dev | Thf-gamma2 analogs and pharmaceutical compositions comprising them |
| JPH07215996A (en) | 1994-01-31 | 1995-08-15 | Torii Yakuhin Kk | B cell epitope against mite allergen |
| HU220344B (en) | 1994-07-05 | 2001-12-28 | Steeno Research Group A/S | Immunomodulators |
| SE9403526D0 (en) | 1994-10-14 | 1994-10-14 | Astra Ab | New Peptides |
-
1994
- 1994-10-14 SE SE9403526A patent/SE9403526D0/en unknown
-
1995
- 1995-09-27 ZA ZA958140A patent/ZA958140B/en unknown
- 1995-10-03 IL IL11550995A patent/IL115509A0/en unknown
- 1995-10-06 PL PL95319631A patent/PL319631A1/en unknown
- 1995-10-06 CZ CZ971119A patent/CZ111997A3/en unknown
- 1995-10-06 EP EP95934921A patent/EP0783519A1/en not_active Withdrawn
- 1995-10-06 EE EE9700087A patent/EE9700087A/en unknown
- 1995-10-06 AU AU37133/95A patent/AU705364B2/en not_active Ceased
- 1995-10-06 US US08/836,480 patent/US6103697A/en not_active Expired - Fee Related
- 1995-10-06 JP JP8513146A patent/JPH10507448A/en active Pending
- 1995-10-06 SK SK467-97A patent/SK46797A3/en unknown
- 1995-10-06 WO PCT/SE1995/001151 patent/WO1996011943A1/en not_active Application Discontinuation
- 1995-10-06 CA CA002201479A patent/CA2201479A1/en not_active Abandoned
- 1995-10-06 MX MX9702666A patent/MX9702666A/en unknown
- 1995-10-06 BR BR9509345A patent/BR9509345A/en not_active Application Discontinuation
- 1995-10-06 HU HU9702044A patent/HUT77118A/en unknown
- 1995-10-12 TR TR95/01255A patent/TR199501255A2/en unknown
-
1997
- 1997-04-08 IS IS4459A patent/IS4459A/en unknown
- 1997-04-09 NO NO971625A patent/NO971625L/en unknown
- 1997-04-10 FI FI971499A patent/FI971499A/en unknown
-
2000
- 2000-05-01 US US09/562,897 patent/US6228374B1/en not_active Expired - Fee Related
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