CN110041404B - Citrullinated antigen modified peptide and application thereof - Google Patents
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Abstract
The invention provides citrullinated antigen modified peptide and application thereof, and relates to the technical field of rheumatoid arthritis treatment, wherein the citrullinated antigen modified peptide has an amino acid sequence shown in SEQ ID No.1 or SEQ ID No. 2. The citrullinated antigen modified peptide is specifically combined with HLA-DRB1 related to rheumatoid arthritis, and the combination of the antigen peptide and HLA-DRB1 is inhibited, so that the activation of T cells is inhibited, and the purpose of treating the rheumatoid arthritis is achieved.
Description
Technical Field
The invention relates to the technical field of rheumatoid arthritis treatment, in particular to citrullinated antigen modified peptide and application thereof.
Background
Rheumatoid arthritis is a systemic autoimmune disease that predominates in chronic progressive joint disease. The pathological changes mainly accumulate in multiple joints of the whole body, and are in the form of multiple and symmetrical chronic synovitis, so that the damage to cartilage and bone is caused, and severe patients can cause joint deformity and even disability. Rheumatoid arthritis is one of the major diseases causing labor loss and disability.
The etiology of rheumatoid arthritis is not clear, and it is widely believed that genetic factors play an important role in the pathogenesis of rheumatoid arthritis. Recent studies on the pathogenesis of rheumatoid arthritis have shown that autoantigen-driven T cell activation is the basis for the pathogenesis and disease progression of rheumatoid arthritis. Antigen polypeptide is identified and presented by antigen presenting cells in vivo, and then is identified by an antigen specific T cell surface T Cell Receptor (TCR), an MHC-antigen peptide-TCR trimolecular complex is formed, antigen specific T and B cells are activated, inflammatory cytokines, immune globulin and the like are increased, synovial inflammation and pannus are caused to be formed, and characteristic pathological changes of rheumatoid arthritis such as cartilage and bone destruction are caused.
At present, no medicine for fundamentally controlling rheumatoid arthritis exists. Clinically, the anti-rheumatism drugs and biological preparations for improving the disease condition are mainly applied to relieve the symptoms, inhibit inflammation, delay joint damage and improve the functions of patients. In recent years, biological agents and small molecule targeted drugs are applied, so that more choices are provided for treating rheumatoid arthritis patients, and the remission rate is further improved. Nevertheless, some patients still have poor therapeutic effect. Biological agents and small molecule targeted drugs are expensive, and bring huge economic burden to patients and society. Moreover, these drugs do not act on the initiation of the disease, and it is difficult to control the disease in a targeted manner. Moreover, there are many adverse reactions such as bone marrow suppression, liver function impairment, and increased risk of infection, which results in many patients not being able to tolerate treatment with these drugs.
Disclosure of Invention
The invention aims to provide citrullinated antigen modified peptide and application thereof, wherein the citrullinated antigen modified peptide is specifically combined with HLA-DRB1 related to rheumatoid arthritis, and is used for inhibiting the combination of antigen peptide and HLA-DRB1, so that the activation of T cells is inhibited, and the purpose of treating rheumatoid arthritis is achieved.
The invention provides citrullinated antigen modified peptide, which has an amino acid sequence shown in SEQ ID No.1 or SEQ ID No. 2.
Preferably, myristic acid is attached to the nitrogen terminus of the citrullinated antigen-modified peptide.
The invention also provides application of the citrullinated antigen modified peptide in the technical scheme in preparation of drugs for preventing and treating rheumatoid arthritis.
Preferably, the medicament also comprises a pharmaceutically acceptable carrier or adjuvant of the citrullinated antigen modified peptide.
Preferably, the dosage form of the medicament comprises tablets, pills, capsules, syrups, powders or solutions.
The invention also provides application of the citrullinated antigen modified peptide in the technical scheme in preparation of a medicament for inhibiting recognition of T cells on antigens.
The invention also provides application of the citrullinated antigen modified peptide in the technical scheme in preparation of a medicament for inhibiting autoimmune reaction caused by recognition of T cells on antigen.
The invention also provides application of the citrullinated antigen modified peptide in the technical scheme in preparation of a drug for blocking combination of T cells and antigen peptide.
The invention also provides application of the citrullinated antigen modified peptide in the technical scheme in preparation of drugs for inhibiting the functions of HLA-DRB1 molecules.
The citrullinated antigen modified peptide has an amino acid sequence shown in SEQ ID No.1 or SEQ ID No.2, is specifically combined with HLA-DRB1 related to rheumatoid arthritis, and inhibits the combination of the antigen peptide and HLA-DRB1, so that the activation of T cells is inhibited, and the purpose of treating the rheumatoid arthritis is achieved.
Drawings
FIG. 1 is citrullinated antigen modified peptide screening;
FIG. 2 is a further demonstration of the effect of aVP3 and aVP5 on IL-6 secretion by PBMCs of rheumatoid arthritis patients;
FIG. 3 shows the inhibition of experimental arthritis by nasal mucosal administration of aVP3 and aVP 5;
fig. 4 is aVP3 and aVP5 inhibiting the development of experimental arthritis by inhibiting Tfh.
Detailed Description
The invention provides citrullinated antigen modified peptide, which has an amino acid sequence shown in SEQ ID No.1 or SEQ ID No.2, and the specific sequence is as follows:
SEQ ID No.1：SAVAL-Cit-SSVPGVR；
SEQ ID No.2：SAVRL-Cit-RSVPGVR。
in the invention, the citrullinated antigen modified peptide is designed according to the following concept:
1. the interaction capacity of the citrullinated antigen modified peptide and HLA is enhanced or unchanged and at least can not be obviously weakened;
2. the interaction capacity of citrullinated antigen modified peptide and TCR capable of recognizing HLA-DRB1 x 04:01 is obviously weakened.
The citrullinated antigen modified peptide is combined with HLA-DRB1 x 04:01 in vivo, but can not cause the activation of corresponding autoreactive T cells, thereby relieving the symptoms of rheumatoid arthritis and even achieving the effect of curing.
In the invention, the citrullinated antigen modified peptide is synthesized by a solid phase synthesis method and purified by a high performance liquid chromatography method by Zhongji Biochemical company Limited and Beijing Saibutsu Gene technology Limited.
According to the invention, the nitrogen terminal of the citrullinated antigen modified peptide is preferably connected with myristic acid, and the specific sequence is as follows:
SEQ ID No.3：Myr-SAVAL-Cit-SSVPGVR；
SEQ ID No.4：Myr-SAVRL-Cit-RSVPGVR。
according to the invention, the nitrogen end of the citrullinated antigen modified peptide is connected with myristic acid, and the myristic acid not only increases the water solubility and stability of the polypeptide, but also can promote the transport and presentation of the polypeptide to cells.
The invention also provides application of the citrullinated antigen modified peptide in the technical scheme in preparation of drugs for preventing and treating rheumatoid arthritis.
In the present invention, the medicament further preferably comprises a pharmaceutically acceptable carrier or adjuvant for citrullinated antigen modified peptide. The invention has no special limitation on the types of the medicinal carrier and the adjuvant, and can adopt the conventional method.
In the present invention, the dosage form of the drug preferably includes a tablet, a pill, a capsule, a syrup, a powder, or a solution. The preparation method of the dosage form of the medicine is not particularly limited, and the conventional preparation method of the dosage form is adopted. The content of the citrullinated antigen modified peptide in the preparation formulation is not particularly limited, and the content of the drug in the conventional preparation formulation is adopted.
The invention also provides application of the citrullinated antigen modified peptide in the technical scheme in preparation of a medicament for inhibiting expression of HLA-DRB1 molecules.
The invention also provides application of the citrullinated antigen modified peptide in the technical scheme in preparation of a medicament for inhibiting recognition of T cells on antigens.
The invention also provides application of the citrullinated antigen modified peptide in the technical scheme in preparation of a medicament for inhibiting autoimmune reaction caused by recognition of T cells on antigen.
The invention also provides application of the citrullinated antigen modified peptide in the technical scheme in preparation of a drug for blocking combination of T cells and antigen peptide.
The invention also provides application of the citrullinated antigen modified peptide in the technical scheme in preparation of drugs for inhibiting the functions of HLA-DRB1 molecules.
The citrullinated antigen modified peptide and the application thereof according to the present invention will be described in further detail with reference to the following specific examples, and the technical solutions of the present invention include, but are not limited to, the following examples.
Example 1
Screening citrullinated antigen modified peptides, wherein 12 citrullinated antigen modified peptides are designed in total, and the method comprises the following steps:
aVP1(SEQ ID No.6：SAVEL-Cit-SSVPGVR)；
aVP2(SEQ ID No.7：SAVDL-Cit-SSVPGVR)；
aVP3(SEQ ID No.3)；
aVP4(SEQ ID No.8：SAVGL-Cit-SSVPGVR)；
aVP5(SEQ ID No.4)；
aVP6(SEQ ID No.9：SAVRL-Cit-FSVPGVR)；
aVP7(SEQ ID No.10：SAVRL-Cit-SSVEGVR)；
aVP8(SEQ ID No.11：SAVRL-Cit-SSVKGVR)；
aVP9(SEQ ID No.12：SAVRL-Cit-SSVWGVR)；
aVP10(SEQ ID No.13：SAVEL-Cit-WSVPGVR)；
aVP11(SEQ ID No.14：SAVDL-Cit-SSVRGVR)；
aVP12(SEQ ID No.15：SAVAL-Cit-KSVFGVR)；
prototype peptide (SEQ ID No. 16: SAVRL-Cit-SSVPGVR).
As can be seen from FIG. 1, the level of IL-6 production by PBMC in the peripheral blood of rheumatoid arthritis patients was elevated under the stimulation with the prototype peptide. While IL-6 levels were significantly reduced under stimulation with the aVP2, aVP3, aVP4, aVP5 and aVP6 allosteric peptides, particularly the aVP3 and aVP5 peptides.
Citrullinated antigen modified peptides aVP3(SEQ ID No.3) and aVP5(SEQ ID No.4), while vimentin 66-78 prototype peptides (myristic acid attached to the nitrogen terminus of the sequence of SEQ ID No. 16) were synthesized (wVP). The polypeptide is synthesized by Zhongtai Biochemical company and Beijing Saibusheng Gene technology company, and purified by solid phase synthesis and high performance liquid chromatography. To facilitate transport of the peptide into the cell, myristic acid was attached to the N-terminus of both the citrullinated antigen modified peptide and the prototype peptide, as shown in table 1. The mass spectrometry result shows that the sequence of the polypeptide is correct, and the purity is over 95 percent.
TABLE 1 synthetic polypeptides and sequences thereof
Wherein, Myr is myristic acid, S is serine, A is alanine, V is valine, R is arginine, L is leucine, Cit is citrulline, P is proline, and G is glycine.
Example 2
Low reactivity of citrullinated antigen-modified peptides in peripheral blood T cells of rheumatoid arthritis patients.
In an embodiment of the present invention, the responsiveness of peripheral blood T cells of patients with rheumatoid arthritis to two citrullinated antigen-modified peptides aVP3 and aVP5 was studied, and the change in the level of production of the inflammatory cytokine IL-6 under the stimulation of allosteric peptides was examined.
Starting with 4mL of blood per patient, the blood was added to 4mL of Ficoll-Paque PLUS in a 15mL centrifuge tube that was centrifuged at 1200rpm for 30 minutes. The corresponding mononuclear cell (PBMC) layer was extracted. Subsequently, cells were washed twice with 15mL of 1 × PBS and after each wash they were centrifuged at 1200 rpm. Finally, the cell pellet was resuspended in RPMI1640 containing 10% fetal bovine serum and penicillin (100U/mL), streptomycin (100. mu.g/mL), 25mM/L HEPES and 2mM L-glutamine (all available from Gibco BRL).
The PBMC obtained was designated 2 × 105The number of cells/well was seeded in 96-well disks (Costar). Subsequently, citrullinated antigen-modified peptide was added at a concentration of 30. mu.g/mL. Phytohemagglutinin (PHA) at 10 μ g/ml was used as a positive control for cell stimulation, while RPMI1640 alone was used as a control for basal cell growth. The culture system for each well was 200. mu.L.
Cells were cultured for 120 hours, and then supernatants from each well were removed to determine the concentration of cytokine IL-6 by using a specific ELISA kit (daceae).
At the same time, 200. mu.l of whole blood of the patient was taken, DNA was extracted by using a blood DNA extraction kit (Tiangen), and the obtained DNA was sent to Beijing Sicheng Biotechnology Co., Ltd. for HLA-DRB1 typing.
IL-6 levels regulated by individual peptide fragments in PBMCs of RA patients are shown in FIG. 2. As observed in figure 2, both aVP3 and aVP5 peptides were able to significantly reduce IL-6 levels compared to wVP peptide, particularly in rheumatoid arthritis patients containing shared epitopes. IL-6 is one of the cytokines that are crucial in the course of rheumatoid arthritis inflammation, and thus this peptide is a potential therapeutic candidate for the treatment of this disease.
Example 3
aVP3 and aVP5 allosteric peptides were evaluated for therapeutic efficacy in an animal model of bovine collagen type II (CII) -induced arthritis.
In this example, in addition to wVP, aVP3, and aVP5, an unrelated peptide (iP) was added. The peptide fragment of the unrelated peptide is the reverse sequence of wVP, Myr-RVGPVSS-Cit-LRVAS (SEQ ID No. 5).
The experimental arthritis model of the present invention employs an internationally recognized collagen arthritis (CIA) model. The experimental animal is an inbred DBA/1 mouse. The experimental mouse is from Beijing Huafukang Biotechnology GmbH. The mice were all bred at the animal testing center (SPF grade) of the people hospital of Beijing university. All experimental mice were male mice of 6-8 weeks old. All procedures related to animals in the experiment are carried out according to the national experimental animal management regulations.
Bovine type II collagen was purchased from Sigma, dissolved in anhydrous glacial acetic acid to give a 3mg/ml solution, emulsified with an equal volume of Freund's complete adjuvant (Sigma), and injected intradermally into the caudal root of each mouse at a dose of 100. mu.l of emulsion, CII was injected at a dose of 150. mu.g/mouse. After 21 days, 3mg/ml bovine type II collagen prepared by dissolving anhydrous glacial acetic acid was emulsified with an equal volume of Freund's incomplete adjuvant (Sigma) in the same manner, and 50. mu.l of the emulsion was injected intradermally into the caudal root of each mouse, and the injection dose of CII was 75. mu.g/mouse. The experiment successfully establishes an arthritis model of a DBA/1 mouse.
Mice were observed daily for swelling of ankle and interphalangeal joints after the second immunization. Arthritis was assessed with a score scale of 0-16 points. Each of the four paws was scored according to 0-4 points, wherein 1-2 toe swellings were scored as 1 point, 3 or more than 3 toe swellings were scored as 2 points, and the paw and ankle swellings were scored as 1 point, respectively. The joint scores of the affected joints were added up to 16 points.
Mice were observed daily for morbidity after the second immunization. The diseased mice were randomly divided into 5 groups of 8-10 mice each. The allosteric peptide, the prototypic peptide, the irrelevant peptide and the aqueous nasal drop treatment were each administered beginning on the day of onset. The dose of allosteric peptide, prototype peptide and irrelevant peptide was 10. mu.l/dose (polypeptide dissolved in water at a concentration of 2.5mg/ml) 1 time per day for 15 consecutive days. The control group was administered with 10. mu.l of nasal drop water each time. Mice were observed daily and the number of arthritic joints was scored using the previously described arthritis assessment method.
The mice were sacrificed 28 days after onset, draining lymph nodes were removed, gently ground into a cell suspension, filtered and removed 1 × 106(100. mu.l) was added to the flow tube, and the flow antibody FVD-eFluor5060.1. mu.l was added thereto, followed by incubation for 20 minutes at room temperature in the absence of light. PBS1ml was added, mixed well and centrifuged at 1500rpm for 5 minutes, and the supernatant was discarded and the following flow antibody was added to each tube: CD4-eFluor 4501. mu.l, CD8-APC-EF 7801. mu.l, CD25-PE-Cy 71. mu.l, 4 degrees were incubated for 30 minutes. Adding PBS1ml, mixing, centrifuging at 1500rpm for 5 min, discarding supernatant, adding 1ml membrane-breaking solution into each tube (concentrated solution: diluted solution ═1:3), treating at room temperature in a dark place for 30 minutes, adding 1 × membrane breaking liquid with the volume more than 2 times, centrifuging at 1500rpm for 5 minutes, removing the supernatant, adding Foxp3-PE-eFluor6102 mu l, incubating at room temperature in a dark place for 1 hour, adding PBS1ml, mixing uniformly, centrifuging at 1500rpm for 5 minutes, removing the supernatant, adding 200ul PBS for resuspension.
Another 1 × 106(100. mu.l) was added to the flow tube and purified rat anti-mouse CXCR5 purified antibody was added at 3ul and incubated at 4 ℃ for 1 hour. PBS1ml was added to each tube, after mixing, centrifugation was carried out at 1500rpm for 5 minutes, and after discarding the supernatant, biotin-conjugated anti-rat IgG 2. mu.l was added thereto, and incubation was carried out at 4 ℃ for 30 minutes. PBS1ml was added, mixed well and centrifuged at 1500rpm for 5 minutes, and the supernatant was discarded and the following anti-mouse flow antibody was added: SA-APC 1 u l, CD3-PEcy72 u l, CD4-Percp Cy5.52 u l, CD8-FITC 2 u l, CD44-APC Cy72 u l and PD-1-PE 2 u l, 4 degrees light-shielding incubation for 30 minutes. PBS1ml is added, after mixing, centrifugation is carried out for 5 minutes at 1500rpm, the supernatant is discarded, and 200. mu.l of PBS is added to each tube for resuspension.
Flow antibody and membrane disruption solutions used in the experiments were from eBioscience.
CD4+ CD25+ Foxp3+ Treg and CD4+ CD44+ PD-1+ CXCR5+ Tfh cells were tested on a computer.
The induction of arthritis was performed on 52 male DBA/1 mice with bovine CII, resulting in different degrees of joint swelling in 45 mice within 1-3 weeks after the second immunization. On the day of arthritis occurrence, mice were randomly divided into 5 groups, and were given modified peptide, prototype peptide, irrelevant peptide and intranasal instillation treatment, respectively, and the number of joints in which arthritis occurred was scored using the aforementioned arthritis evaluation method.
The results showed no significant difference in time to onset and pre-treatment arthritis scores for each group of mice. aVP5 peptide treated group had a plateau in joint score after 1 week of treatment, while other groups of mice, particularly the unrelated peptide group, had progressively more swelling in the joints (FIG. 3). After the experiment, flow detection analysis of lymph node cells can show that the Tfh of the modified peptide group is reduced compared with that of the water group (figure 4). And Tfh is associated with antibody production by B cells. These results indicate that nasal mucosal administration of citrullinated antigen-modified peptide can reduce autoimmune inflammation in CIA mice, decrease Tfh cells that assist B cells in producing antibodies, and inhibit the degree of arthritis. The polypeptide has therapeutic effect on rheumatoid arthritis by nasal mucosa administration.
From the above examples, it can be seen that the citrullinated antigen-modified peptide specifically binds to HLA-DRB1 associated with rheumatoid arthritis and inhibits the binding of the antigen peptide to HLA-DRB1, thereby inhibiting the activation of T cells and achieving the purpose of treating rheumatoid arthritis.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Sequence listing
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Peking University
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Claims (3)
1. The citrullinated antigen modified peptide has an amino acid sequence shown in SEQ ID No. 2.
2. The use of claim 1, wherein the medicament further comprises a citrullinated antigen modified peptide in a pharmaceutically acceptable carrier or adjuvant.
3. Use according to claim 1 or 2, wherein the medicament is in the form of tablets, pills, capsules, syrups, powders or solutions.
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| CN110041404A (en) | 2019-07-23 |
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