CN102718837A - Short peptide, immunosuppressant containing short peptide, and applications - Google Patents
Short peptide, immunosuppressant containing short peptide, and applications Download PDFInfo
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- CN102718837A CN102718837A CN2012101409505A CN201210140950A CN102718837A CN 102718837 A CN102718837 A CN 102718837A CN 2012101409505 A CN2012101409505 A CN 2012101409505A CN 201210140950 A CN201210140950 A CN 201210140950A CN 102718837 A CN102718837 A CN 102718837A
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Abstract
The invention discloses a short peptide, an immunosuppressant containing the short peptide, and applications. The short peptide is hexapeptide, the amino acid sequence of the short peptide is Trp-Pro-Ala-Pro-Ile-Phe. The short peptide can be used to prepare a medicament which can antagonize interaction between antagonism Fc gamma IIA receptor (Fc gamma RIIA) and immunoglobulin G (IgG) and prepare medicament for treating or preventing autoimmune disease. The short peptide provided in the invention has the characteristics of strong specificity, short composition, low immunogenicity and simple synthesis. The medicament adopting the short peptide as an active component can specifically antagonize interaction between the Fc gamma RIIA and the IgG, rather than antagonize interaction between Fc gamma RI and IgG, therefore the side-effect of the medicament is low. The medicament can be widely applied in manufacture of novel immunosuppressants, and will bring huge social and economic benefits.
Description
The application is dividing an application of following application: the applying date: on April 24th, 2009, and application number: 200910049954.0, invention and created name: a kind of small peptide and contain its immunosuppressor and application.
Technical field
The invention belongs to field of medicaments, particularly a kind of small peptide and contain its immunosuppressor and application.
Background technology
The autoimmune disorder that antibody produces be one type because the autoantibody generation causes organizing, the autoimmune disorder of cell injury.It comprises multiple disease, like the comparatively common systemic lupus erythematous that has, and rheumatoid arthritis, multiple sclerosis, anti-neutrophil leucocyte antibody (Anti-Neutrophil Cytoplasmic Antibody, ANCA) dependency polyangitis.These diseases all are one type of chronic progress, the disease that prognosis is relatively poor.The pathogenesis of the autoimmune disorder that produces for antibody in recent years, is also unclear fully.But acceptor that some are important and cell pathway play keying action in the incidence and development of the autoimmune disorder that antibody produces.Like Fc γ acceptor (Fc γ receptor, Fc γ R) is the bridge of mediation humoral immunization and cellular immunization, and promptly it has mediated the immunologic injury of activated immune cell that autoantibody causes and tissue, cell, causes the acute inflammatory reaction and the chronic progress of disease.
The treatment of the autoimmune disorder that antibody produces like systemic lupus erythematous, rheumatoid arthritis, multiple sclerosis, ANCA dependency vasculitis etc., is the treatment difficult point of modern medicine, in case diagnosis, often prognosis is relatively poor.Along with glucocorticosteroid and the immunosuppressor extensive and regular application in the treatment of autoimmune diseases that antibody produces in recent years, the prognosis of such disease has obtained obvious improvement, and especially the patient's 5 years survival rates have obtained to significantly improve.But along with going deep into of treatment and research, the defective of the regimen of glucocorticosteroid+immunosuppressor appears day by day.Its spinoff is big; Can cause substance metabolism and water and salt metabolic disturbance like glucocorticosteroid, bring out and increase the weight of to infect (this is the major reason that causes death), cause the complication of each system; Bring out psychological problem; Cause cataract glaucoma etc., and immunosuppressant spinoff more is not less than glucocorticosteroid, is especially causing malignant tumour, hemopoietic system dysfunction, sexual gland inhibition etc.These have all hindered the application of glucocorticosteroid+immunosuppressor on the autoimmune disorder that treatment antibody produces greatly.
At present, how reducing the spinoff that glucocorticosteroid and immunosuppressor produce in the autoimmune disorder that treatment antibody produces, is the problem that the clinician pays close attention to the most.Through the lots of clinical test, standard, rational Application glucocorticosteroid and immunosuppressor have reduced its spinoff to a certain extent, but can not address this problem at all.Therefore, more and more researchers begins to pay close attention to the stronger biotype immunosuppressive drug of specificity, and like Rituximab, biotype pharmacy such as A Baxipu all are the very strong immunosuppressor of specificity.These medicines progressively obtain to use in the treatment of autoimmune disorder, and show outstanding hypotoxicity reaction, the characteristics of hypersensitivity.But because the patent of these medicines is mostly by external grasp, and medical expense is expensive, has limited the widely application of these medicines in China.Therefore, the medicine of the autoimmune disorder that produces of the new treatment antibody of exploitation becomes a urgent problem.
By the autoimmune disorder of antibody generation, like systemic lupus erythematous, anaphylactoid purpura, all there are a large amount of autoantibodies in autoimmune disorders such as ANCA dependency vasculitis.The titre of antibody is relevant with severity of disease in its serum, and antibody titers descends when disease takes a turn for the better, and antibody titers rises during recurrence.Fc γ R is the immunoglobulin receptor that all express on nearly all immunocyte film surface, participates in the immunoreation of a series of physiology and pathology, in immune adjusting, also plays keying action.TG19320 (a kind of can through combining IgG Fc section the interactional polypeptide between antagonism Fc γ R and the IgG) can antagonism Fc γ R and IgG between interaction; Thereby the tissue injury of securing system property lupus erythematosus mouse; Reduce its mortality ratio (Nat Biotechnol; 2000,18 (7): 735-739).TG19320 also can intervene the effect of ANCA to normal neutrophil leucocyte; Reduce ANCA inductive neutrophil apoptosis and activation (Chinese Journal of Nephrology; 2006,22 (8): 483-487, Chinese rheumatology magazine; 2007,11 (5): 267-270).But Fc γ R is also serving as the invasion of body opposing pathogenic micro-organism, keeps homeostatic effect, and the effect of blocking Fc γ R fully may cause serious consequence.Thereby can like the specific effect of blocking Fc γ RIIA and IgG, treat autoimmune disorder through the combining of blocking part Fc γ R and antibody.Fc γ RIIA (being Fc γ IIA acceptor) is a hypotype among the Fc γ R, is the important acceptor of the autoimmune disorder of mediate antibody generation, in disease development, plays an important role.Therefore the interaction between antagonism Fc γ RIIA and the IgG has become one of important target spot of the autoimmune disorder of treating the antibody generation, and autoimmune disorder can treated or prevent to the combination of antagonism Fc γ RIIA and IgG.
Summary of the invention
Therefore; The technical problem that the present invention will solve is exactly to exist in the medicine to the autoimmune disorder of existing treatment antibody generation to be difficult for producing; Production cost is high, and expensive deficiency provides a kind of medicine of new treatment autoimmune disorder; This medicine can specificity antagonism Fc γ RIIA and IgG interact, thereby the autoimmune disorder that prevention or treatment antibody produce.
The inventor finds through the research back, does not influence the function of other acceptors through the immunoglobulin receptor Fc γ RIIA of specificity antagonism immunocyte film, is the important target spot of the relevant autoimmune disorder of treatment antibody.Therefore, the inventor is a target with the proteic extracellular fragment of Fc γ RIIA, and a kind of small peptide that designs and synthesizes is found that this small peptide can specificity antagonism IgG and the interaction of Fc γ RIIA, thereby accomplished the present invention.
The present invention solves the problems of the technologies described above one of technical scheme of being adopted: a kind of small peptide, and it is 6 peptides, its aminoacid sequence is to be selected from Thr (Threonine); Pro (proline(Pro)), Ala (L-Ala), Ile (Isoleucine); Phe (phenylalanine(Phe)); His (Histidine), Trp (tryptophane), the combination of the random order of any 6 seed amino acid residues among Tyr (tyrosine) or the Glu (L-glutamic acid).
According to the present invention, preferable, the aminoacid sequence of described small peptide is to be selected from a kind of in the following aminoacid sequence: J-Pro-Ala-Pro-Ile-R, and wherein J represents Thr, His, Trp or Glu amino-acid residue, and R represents Phe or Tyr amino-acid residue; Preferably; Described aminoacid sequence is to be selected from a kind of in the following aminoacid sequence: Thr-Pro-Ala-Pro-Ile-Phe; His-Pro-Ala-Pro-Ile-Phe, Trp-Pro-Ala-Pro-Ile-Phe, Trp-Pro-Ala-Pro-Ile-Tyr and Glu-Pro-Ala-Pro-Ile-Phe.
According to the present invention; Preferable; The aminoacid sequence of described small peptide preferable for being selected from a kind of in the following aminoacid sequence: Pro-Ile-Phe-Ala-Pro-Thr, Phe-Ile-Pro-Pro-Thr-Ala, Pro-Phe-Ile-Ala-Thr-Pro and Pro-Pro-Phe-Thr-Ala-Ile.
Small peptide of the present invention can adopt known method of the prior art to obtain.Both can carry out chemosynthesis, can short peptide sequence be derived into nucleotide sequence again, and be cloned into then and carry out biosynthesizing in the expression vector with the polypeptide automatic DNA synthesizer DNA.
The present invention solves the problems of the technologies described above two of the technical scheme that adopted: a kind of immunosuppressor, its activeconstituents comprises described small peptide.
Immunosuppressor of the present invention contains the small peptide of the present invention of treating significant quantity.When needing, also can also contain other activeconstituents.Can also contain one or more pharmaceutically acceptable carriers in the above-mentioned immunosuppressor.Said carrier comprises thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier and the lubricant etc. that pharmaceutical field is conventional.Immunosuppressor of the present invention can be processed various ways such as tablet, pulvis, granula, capsule, oral liquid and injection liquid, and various formulations all can be by the ordinary method preparation of pharmaceutical field.
Small peptide of the present invention has the activity that combines Fc γ RIIA, and experiment in vitro confirms to have specificity antagonism Fc γ RIIA and the interactional ability of IgG, is Fc γ RIIA antagonist.Therefore small peptide of the present invention can be used for preparing antagonism Fc γ IIA acceptor (Fc γ RIIA) and the interactional medicine of immunoglobulin G (IgG), especially for preparation Fc γ RIIA antagonist.This medicine suppresses tissue, cell injury and the acute inflammatory condition of antibody-mediated autoimmune disorder through the antagonistic action to Fc γ RIIA; Thereby the progress of the autoimmune disorder of blocking antibody mediation, and then prevent or treat antibody-mediated autoimmune disorder.Therefore small peptide of the present invention can be used for preparing the medicine of prevention or treatment autoimmune disorder.What described autoimmune disorder was preferable is systemic lupus erythematous, rheumatoid arthritis, multiple sclerosis and ANCA dependency vasculitis etc.
Raw material that the present invention is used or reagent except that specifying, all commercially available getting.
Than prior art, beneficial effect of the present invention is following: small peptide of the present invention has high specificity, and structure is short and small, and immunogenicity is low, and is synthetic simple, and has stronger inhibition IgG monomer and Fc γ RIIA bonded ability.Can be used for preparing the medicine of antagonism Fc γ RIIA and interactional medicine of IgG and preparation autoimmune disorder.With small peptide of the present invention is the medicine of activeconstituents, can specificity antagonism Fc γ RIIA and IgG between interaction, and the not effect between antagonism Fc γ RI and the IgG.Therefore its spinoff is low.In making neotype immunosuppressant, will be used widely, and will bring huge social and economic benefit.
Description of drawings
Below in conjunction with description of drawings characteristic of the present invention and beneficial effect.
Fig. 1 is that No. 1 small peptide of the present invention of different concns is to Fc γ RIIA and the interactional influence of IgG.
Fig. 2 forms experiment microscopically photo for rosettes.The positive control group of figure A, figure B are the IgG group, and figure C is No. 1 small peptide, and figure D is No. 2 small peptides, and figure E is No. 3 small peptides, and figure F is No. 4 small peptides, and figure G is No. 5 small peptides, and figure H is No. 6 small peptides.
Rosettes formed and inchoate K562 cell count during Fig. 3 respectively organized in the experiment for rosettes forms.1 ~ 6 is 1 ~ No. 6 small peptide.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer." room temperature " described in the embodiment is meant the temperature of the operation room that makes an experiment, and is generally 10 ~ 25 ℃.
The design of embodiment 1 short peptide sequence and synthetic
Through obtaining 9 small peptides after sequences Design, optimization and the screening, see table 1.It is biochemical synthetic to deliver the Shanghai gill, and purity is equal>95%, be used for the test of following examples.
The small peptide that table 1. obtains through design, optimization
The interaction of embodiment 2 short peptide compound specificity antagonism Fc γ RIIA of the present invention and IgG
Used small peptide is: 1 ~ No. 5 small peptide.
(1) cell cultures
U937 cell (Chinese Academy of Sciences's cell bank is bought from Shanghai) adopts the RMPI1640 nutrient solution that contains 10% (v/v) calf serum, at 37 ℃, and 5% (v/v) CO
2Cultivate.K562 cell (Chinese Academy of Sciences's cell bank is bought from Shanghai) adopts the IMDM nutrient solution that contains 10% (v/v) foetal calf serum, 100U/ml penicillium mould and 100 μ g/ml Streptomycin sulphates, at 37 ℃, and 5% (v/v) CO
2Cultivate.
(2) the short peptide compound antagonism Fc γ RIIA-IgG active mensuration that interacts
Utilize the combination situation of flow cytometry method counting cells surface Fc γ R and IgG.
Concrete steps: get the cell that is in the multiplication phase, aseptic PBS washes 3 times, with PBS resuspension to 1 * 10
6/ ml.Negative control group does not add human IgG and small peptide, with the negative contrast of isopyknic PBS.Positive controls adds human IgG (Sigma) 50 μ g/ml, hatches 30min under the room temperature, and PBS washes 2 times.The small peptide intervention group adds synthetic small peptide 200 μ g/ml incubated at room 30 minutes earlier, adds human IgG 50 μ g/ml again, hatches 30min under the room temperature again, and PBS washes 2 times.Lucifuge is hatched 30min under last 3 groups of anti-human IgG Fab section antibody (Sigma) room temperatures that respectively add the FITC mark, and PBS washes 2 times, and 1% (w/v) Paraformaldehyde 96-PBS fixes.Flow cytometry counting fluorescence positive cells number.10000 cells of each sample counting are got the per-cent of positive cell and grand total cell and are represented positive rate, and each sample is established 3 multiple holes, repeated experiments 1 time, and statistics adopts chi square test.
(3) result
Flow cytometry counting cells positive rate is seen table 2.Negative control group is compared with other groups, and difference all has statistical significance.In the k562 groups of cells, positive controls is compared with No. 1, No. 5 small peptides, and difference has statistical significance (P < 0.05), compares with other groups, and difference does not have statistical significance, but still more positive group of the positive cell number of No. 2 small peptide groups is low.In the U937 groups of cells, positive cell group and the equal no difference of science of statistics of other small peptide intervention group (P>0.05).
Table 2. flow cytometry counting cells positive rate
Annotate: a: have statistical significance (p < 0.05) than difference with negative control group; B: have statistical significance (p < 0.05) than difference with positive controls.
The U937 cell is expressed Fc γ RI and Fc γ RIIA acceptor simultaneously, and the K562 cell is only expressed Fc γ RIIA acceptor, and Fc γ RI acceptor is high-affinity receptor, can be preferential and the IgG combination.The U937 cell is as the carrier cell of Fc γ RI acceptor, and the K562 cell is observed the specific inhibition function of small peptide to these two kinds of acceptors as the carrier cell of Fc γ RIIA acceptor.Account for the ratio of total cell through the flow cytometry positive cell; Find small peptide can block the combination of IgG and K562 cell and can not block the combination of IgG and U937 cell; Explain that the novel small peptide of synthetic can specific inhibition Fc γ RIIA acceptor, and can not block Fc γ RI acceptor.
Embodiment 3 small peptides can get the combination between the antagonism Fc γ RIIA-IgG by concentration dependent
Used small peptide is No. 1 peptide.
(1) cell cultures
The K562 cell adopts the IMDM nutrient solution that contains 10% (v/v) foetal calf serum, 100U/ml penicillium mould and 100 μ g/ml Streptomycin sulphates, at 37 ℃, and 5% (v/v) CO
2Cultivate.
(2) act between the CELL ELISA checking small peptide concentration dependent antagonism Fc γ RIIA-IgG
96 orifice plates are with 2% (w/v) PBS-B (2% (w/v) PBS-B is that the bovine serum albumin (BSA) with 2g is dissolved among the 100ml PBS, and is all similar below) sealing, and 4 ℃ are spent the night or room temperature 2h.The K562 cell of taking the logarithm vegetative period is washed 3 times with 1% (w/v) PBS-B.1% (w/v) PBS-B resuspension K562 cell is transferred concentration to 6 * 10
6/ ml, every hole adds K562 cell 100 μ l, removes supernatant after centrifugal.The IgG group directly adds the concentration gradient of IgG, is respectively 5000 μ g/ml, 1000 μ g/ml, 100 μ g/ml, 50 μ g/ml.The small peptide group adds earlier small peptide, and concentration is for being respectively 10 μ g/ml, 100 μ g/ml, and incubated at room added identical IgG concentration gradient after 30 minutes, hatched 60min for 37 ℃.Wash 3 times with 1% (w/v) PBS-B, add rabbit anti-human igg's antibody (Sigma) of horseradish peroxidase (HRP) mark, hatch 30min for 37 ℃.1% (w/v) PBS-B washes 3 times, with the colour developing of ABTS colouring reagents box (worker is given birth in Shanghai), and the operation of concrete development step peace specification sheets.BioTek ELIASA 405nm wavelength reads the OD value.
(3) result
IgG concentration gradient group does not add any small peptide, and 10 μ g/ml small peptide groups add 10 μ g/ml small peptides, and 100 μ g/ml small peptide groups add 100 μ g/ml small peptides.With the ordinate zou is 405nm place light absorption value, and X-coordinate is that the logarithmic value of IgG concentration is drawn, and the result sees Fig. 1.Can find out obviously that from figure in the IgG group, with the concentration increase of IgG, the OD value obviously rises, and explains that the combination of IgG and Fc γ RIIA increases, and is concentration dependent.In the small peptide group that adds 10 μ g/ml and 100 μ g/ml, find that the OD value still along with increasing of IgG concentration, but compare with the IgG group; Under the same concentrations; Its OD value descends, and small peptide 100 μ g/ml group than the decline of small peptide 10 μ g/ml group OD value obviously explains that the combination of small peptide antagonism IgG and Fc γ RIIA acceptor also has concentration dependent; Along with increasing of small peptide concentration, antagonistic ability strengthens.
Embodiment 4 small peptide blocking-up K562 cells of the present invention form the rosettes experiment
Used small peptide: 1 ~ No. 6 small peptide.
(1) cell cultures
The K562 cell adopts the IMDM nutrient solution that contains 10% (v/v) foetal calf serum, 100U/ml penicillium mould and 100 μ g/ml Streptomycin sulphates, at 37 ℃, and 5% (v/v) CO
2Cultivate.
(2) preparation of EA
Get 4% (v/v) sheep red blood cell (SRBC) suspension and add in the test tube, add the anti-sheep red blood cell (SRBC) antibody of rabbit of (1 ︰ 1000) dilution of equivalent again, mixing; Put 15min in 37 ℃ of water-baths; With Hank ' s liquid washing 2 times, with isopyknic Hank ' s liquid resuspension, be the EA suspension again.
(3) rosettes forms experiment
If 3 groups, be respectively positive group, IgG group, small peptide group.
Concrete steps:
The K562 cell of taking the logarithm vegetative period is washed 3 times with HBSS, resuspension, and transferring cell concn is 4 * 10
6Cell/ml.
Positive group: get K562 cell suspension 0.1ml in the EP pipe, add 0.1ml the EA suspension, mixing.
IgG group: get K562 cell suspension 0.1ml in the EP pipe, add human IgG 20 μ g earlier, add the EA suspension of 0.1ml again, mixing.
Small peptide group: get K562 cell suspension 0.1ml in the EP pipe, add patent earlier and require 1 small peptide and patent to require 2 small peptides, 20 μ g, add the EA suspension of 0.1ml again, mixing.
4 ℃, 2h leaves standstill, and has hanged sedimentation cell gently, gets 20 μ l cell suspensions, uses the cell counting count board smear, a plurality of visuals field of microscopically picked at random, and the counting rosettes forms and inchoate K562 cell.
(4) rosettes forms experimental result
With the K562 cell of cell counting count board counting more than 200, be the rosettes positive cell to combine 5 above sheep red blood cell (SRBC)s on 1 K562 cell, the microscopically photo is seen Fig. 2.Counting rosettes positive cell accounts for the per-cent of total cell count, and the result sees Fig. 3.As can be seen from the figure the rosettes positive rate of positive controls is high; And 1 K562 cell peripheral is around a large amount of sheep red blood cell (SRBC)s; And the rosettes positive cell of IgG group and No. 1, No. 2, No. 5, No. 6 small peptide group reduces; And most of K562 cell bonded sheep red blood cell (SRBC) reduces than positive control; This explanation IgG group, No. 1 small peptide group, No. 2 small peptide groups, No. 4 small peptide groups, No. 5 small peptide groups, No. 6 small peptide groups all can reduce the rosette forming rate of K562 cell, and visible small peptide of the present invention has the interaction between antagonism Fc γ RIIA and the IgG.
Claims (4)
1. a small peptide is characterized in that, its aminoacid sequence is Trp-Pro-Ala-Pro-Ile-Phe.
2. an immunosuppressor is characterized in that, its activeconstituents comprises the described small peptide of claim 1.
3. according to claim 1 or claim 2 the application of small peptide in preparation Fc γ IIA receptor antagonist.
4. claim 1 or the 2 described small peptides application in preparation antagonism Fc γ IIA acceptor and the interactional medicine of immunoglobulin G.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101409505A CN102718837A (en) | 2009-04-24 | 2009-04-24 | Short peptide, immunosuppressant containing short peptide, and applications |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101409505A CN102718837A (en) | 2009-04-24 | 2009-04-24 | Short peptide, immunosuppressant containing short peptide, and applications |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200910049954 Division CN101870723B (en) | 2009-04-24 | 2009-04-24 | Short peptide and immunosuppressant containing the same and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102718837A true CN102718837A (en) | 2012-10-10 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012101409505A Pending CN102718837A (en) | 2009-04-24 | 2009-04-24 | Short peptide, immunosuppressant containing short peptide, and applications |
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|---|---|
| CN (1) | CN102718837A (en) |
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2009
- 2009-04-24 CN CN2012101409505A patent/CN102718837A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 徐春厚等: "《动物免疫学实验指导（第二版）》", 31 December 2007 * |
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Application publication date: 20121010 |