CN102718836B - Short peptide, immune inhibitor containing the same and application thereof - Google Patents
Short peptide, immune inhibitor containing the same and application thereof Download PDFInfo
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- CN102718836B CN102718836B CN201210140942.0A CN201210140942A CN102718836B CN 102718836 B CN102718836 B CN 102718836B CN 201210140942 A CN201210140942 A CN 201210140942A CN 102718836 B CN102718836 B CN 102718836B
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Abstract
The invention discloses a short peptide, an immune inhibitor containing the same and an application thereof. The short peptide is a hexapeptide and its amino acid sequence is Glu-Pro-Ala-Pro-Ile-Phe. The short peptide can be used for preparing medicines for antagonizing interaction between an Fc IIA receptor (FcGamma RIIA) and immune globulin G (IgG) and medicines for treating or preventing autoimmune diseases. The short peptide has the characteristics of strong specificity, short and small structure, low immunogenicity and simple synthesis. Medicines with the short peptide of the invention as an active ingredient can antagonize the interaction between FcGamma RIIA and IgG with their specificity but without antagonizing the interaction between FcGamma RI and IgG, thus having low side effect. The short peptide provided by the invention will be widely used in preparing novel immune inhibitors and thus bring great 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 the immunosuppressor that contains it and application.
Technical field
The invention belongs to field of medicaments, particularly a kind of small peptide and the immunosuppressor that contains it and application.
Background technology
The autoimmune disorder that antibody produces is that a class is because autoantibody produces the autoimmune disorder that causes tissue, cell injury.It comprises various diseases, as comparatively common are systemic lupus erythematous, and rheumatoid arthritis, multiple sclerosis, anti-Antineutrophil antibody (Anti-Neutrophil Cytoplasmic Antibody, ANCA) associated small vessel vasculitis.These diseases are all the chronic progress of a class, the disease that prognosis is poor.The pathogenesis of the autoimmune disorder producing for antibody in recent years, is also completely unclear.But play keying action in the developing of the autoimmune disorder that the acceptor that some are important and cell pathway produce at antibody.If Fc γ acceptor (Fc γ receptor, Fc γ R) is the bridge of humoral immunity and cellular immunization, it has mediated the immunologic injury of activated immune cell that autoantibody causes and tissue, cell, causes acute inflammatory reaction and the chronic progress of disease.
The treatment of the autoimmune disorder that antibody produces, as systemic lupus erythematous, rheumatoid arthritis, multiple sclerosis, ANCA dependency vasculitis etc., is the treatment difficult point of modern medicine, once diagnosis, often prognosis is poor.Along with the extensive and regular application in the treatment of autoimmune diseases that glucocorticosteroid and immunosuppressor produce at antibody in recent years, the prognosis of such disease has obtained obvious improvement, and especially patient's 5 years survival rates, have obtained and significantly improved.But along with going deep into for the treatment of and research, the defect of the treatment plan of glucocorticosteroid+immunosuppressor appears day by day.Its side effect is large, as glucocorticosteroid can cause substance metabolism and water and salt metabolic disturbance, 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 mental anomaly, cause cataract glaucoma etc., and immunosuppressant side effect is more 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 in the autoimmune disorder for the treatment of antibody generation greatly.
At present, how reducing the side effect that glucocorticosteroid and immunosuppressor produce in the autoimmune disorder for the treatment of antibody generation, is the problem that clinician pays close attention to the most.By a large amount of clinical trials, standard, rationally apply glucocorticosteroid and immunosuppressor and reduced to a certain extent its side effect, but can not address this problem at all.Therefore, increasing investigator starts to pay close attention to the biotype immunosuppressive drug that specificity is stronger, and as Rituximab, the biotype pharmacy such as Orencia, are all the immunosuppressor that specificity is very strong.These medicines progressively obtain application in the treatment of autoimmune disorder, and show outstanding hypotoxicity reaction, the feature of hypersensitivity.But because the patent of these medicines is mostly by abroad grasping, and medical expense is expensive, has limited the widely application of these medicines in China.Therefore the medicine of, developing the autoimmune disorder that new treatment antibody produces becomes a urgent problem.
The autoimmune disorder being produced by antibody, as systemic lupus erythematous, anaphylactoid purpura, all there are a large amount of autoantibodies in the autoimmune disorders such as ANCA dependency vasculitis.The titre of its Serum Antibody is relevant with the seriousness of disease, and when disease takes a turn for the better, antibody titers declines, 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 immune response of a series of physiology and pathology, also plays keying action in immune adjusting.Mono-kind of TG19320(can by conjunction with IgG Fc section the interactional polypeptide between antagonism Fc γ R and IgG) can antagonism Fc γ R and IgG between interaction; thereby the tissue injury of securing system 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 neutrophil apoptosis and the activation (Chinese Journal of Nephrology of ANCA induction, 2006,22 (8): 483-487, China's 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 completely may cause serious consequence.Thereby can, by the combination of blocking part Fc γ R and antibody, as the effect of specific blocking-up Fc γ RIIA and IgG, treat autoimmune disorder.Fc γ RIIA(is Fc γ IIA acceptor) be a hypotype in Fc γ R, be the important acceptor of the autoimmune disorder of mediate antibody generation, in disease development, play an important role.Therefore the interaction between antagonism Fc γ RIIA and IgG has become one of important target spot of the autoimmune disorder for the treatment of antibody generation, and the combination of antagonism Fc γ RIIA and IgG can be treated or prevention of autoimmune diseases.
Summary of the invention
Therefore, the technical problem to be solved in the present invention is exactly to exist and be difficult for producing in the medicine for the autoimmune disorder of existing treatment antibody generation, production cost is high, expensive deficiency, a kind of medicine of new treatment autoimmune disorder is provided, this medicine can specificity antagonism Fc γ RIIA and IgG interact, thereby the autoimmune disorder that prevention or treatment antibody produce.
The inventor finds after research, does not affect the function of other acceptors by the immunoglobulin receptor Fc γ RIIA of specificity antagonism immunocyte film, is the important target spot of the autoimmune disorder that treatment antibody is relevant.Therefore, it is target that the inventor be take the extracellular fragment of Fc γ RIIA albumen, and a kind of small peptide designing and synthesizing is found that this small peptide can specificity antagonism IgG and the interaction of Fc γ RIIA, thereby completed the present invention.
The present invention solves the problems of the technologies described above one of adopted technical scheme: a kind of small peptide, it is 6 peptides, its aminoacid sequence is to be selected from Thr(Threonine), Pro(proline(Pro)), Ala(L-Ala), Ile(Isoleucine), Phe(phenylalanine), His(Histidine), Trp(tryptophane), Tyr(tyrosine) or Glu(L-glutamic acid) in the combination of random order of any 6 seed amino acid residues.
According to the present invention, preferably, the aminoacid sequence of described small peptide is to be selected from a kind of in following aminoacid sequence: J-Pro-Ala-Pro-Ile-R, and wherein J represents Thr, His, Trp or Glu amino-acid residue, R represents Phe or Tyr amino-acid residue; Preferably, described aminoacid sequence is to be selected from a kind of in 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, preferably, the aminoacid sequence of described small peptide is preferably for being selected from a kind of in 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 with polypeptide automatic DNA synthesizer DNA, short peptide sequence can be derived into nucleotide sequence again, and then be cloned into and in expression vector, carry out biosynthesizing.
The present invention solves the problems of the technologies described above two of adopted technical scheme: a kind of immunosuppressor, its activeconstituents comprises described small peptide.
Immunosuppressor of the present invention contains the small peptide of the present invention for the treatment of significant quantity.When needing, also can also contain other activeconstituents.In above-mentioned immunosuppressor, can also contain one or more pharmaceutically acceptable carriers.Described carrier comprises thinner, vehicle, weighting agent, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier and the lubricant etc. of pharmaceutical field routine.Immunosuppressor of the present invention can be made the 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 in conjunction with 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 is by suppressing tissue, cell injury and the acute inflammatory condition of antibody-mediated autoimmune disorder to the antagonistic action of 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 the medicine of preparation prevention or treatment autoimmune disorder.Described autoimmune disorder is preferably systemic lupus erythematous, rheumatoid arthritis, multiple sclerosis and ANCA dependency vasculitis etc.
The raw material that the present invention is used or reagent except special instruction, equal commercially available obtaining.
Than prior art, beneficial effect of the present invention is as follows: small peptide of the present invention has high specificity, and structure is short and small, and immunogenicity is low, synthetic simple, and has the ability of stronger inhibition IgG monomer and Fc γ RIIA combination.Can be used for preparing the medicine of antagonism Fc γ RIIA and the interactional medicine of IgG and preparation autoimmune disorder.The medicine that the small peptide of the present invention of take is activeconstituents, can specificity antagonism Fc γ RIIA and IgG between interaction, and the not effect between antagonism Fc γ RI and IgG.Therefore its side effect is low.In manufacturing neotype immunosuppressant, will be used widely, and will bring huge society and economic benefit.
Accompanying drawing explanation
Below in conjunction with accompanying drawing, feature of the present invention and beneficial effect are described.
Fig. 1 is that No. 1 small peptide of the present invention of different concns is on Fc γ RIIA and the interactional impact of IgG.
Fig. 2 is that rosettes forms photo under experiment microscope.The positive control group of figure A, figure B is 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.
Fig. 3 is that rosettes forms in experiment rosettes in each group and forms and inchoate K562 cell count.1 ~ 6 is 1 ~ No. 6 small peptide.
Embodiment
With embodiment, further illustrate the present invention below, but the present invention is not limited.The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition, or the condition of advising according to manufacturer." room temperature " described in embodiment refers to the temperature of the operation room of testing, and is generally 10 ~ 25 ℃.
The design of embodiment 1 short peptide sequence and synthetic
After sequences Design, optimization and screening, obtain 9 small peptides, in Table 1.Deliver Shanghai gill biochemical synthetic, the equal >95% of purity, for the test of following examples.
The small peptide that table 1. obtains through Design and optimization
The interaction of embodiment 2 short peptide compound specificity of the present invention antagonism Fc γ RIIA and IgG
Small peptide used is: 1 ~ No. 5 small peptide.
(1) cell cultures
U937 cell (buying from Shanghai Chinese Academy of Sciences cell bank), adopts the RMPI1640 nutrient solution containing 10% (v/v) calf serum, at 37 ℃, and 5% (v/v) CO
2cultivate.K562 cell (buying from Shanghai Chinese Academy of Sciences cell bank), adopts the IMDM nutrient solution containing 10% (v/v) foetal calf serum, 100U/ml penicillin 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 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, under room temperature, hatches 30min, and PBS washes 2 times.Small peptide intervention group first adds synthetic small peptide 200 μ g/ml incubated at room 30 minutes, then adds human IgG 50 μ g/ml, then hatches 30min under room temperature, and PBS washes 2 times.Under last 3 groups of anti-human IgG Fab section antibody (Sigma) room temperatures that respectively add FITC mark, lucifuge is hatched 30min, and PBS washes 2 times, and 1%(w/v) paraformaldehyde-PBS fixes.The cell count of the flow cytometry counting fluorescence positive.10000 cells of each sample counting, the per-cent of getting positive cell and grand total cell represents positive rate, and each sample is established 3 multiple holes, repeats to test 1 time, and statistics adopts chi square test.
(3) result
Flow cytometry counting cells positive rate is in Table 2.Negative control group is compared with other groups, and difference all has statistical significance.In 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, difference does not have statistical significance, but still more positive group low of the positive cell number of No. 2 small peptide groups.In 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
Note: a: and negative control group has statistical significance (p<0.05) than difference; B: and positive controls has statistical significance (p<0.05) than difference.
U937 cell is expressed Fc γ RI and Fc γ RIIA acceptor simultaneously, and K562 cell is only expressed Fc γ RIIA acceptor, and Fc γ RI acceptor is high-affinity receptor, can preferential and IgG combination.U937 cell is as the carrier cell of Fc γ RI acceptor, and K562 cell, as the carrier cell of Fc γ RIIA acceptor, is observed the specific inhibition function of small peptide to these two kinds of acceptors.By flow cytometry positive cell, account for the ratio of total cell, find small peptide can block the combination of IgG and K562 cell and can not block the combination of IgG and U937 cell, illustrate that synthetic novel small peptide can specific inhibition Fc γ RIIA acceptor, and can not block Fc γ RI acceptor.
Small peptide used is No. 1 peptide.
(1) cell cultures
K562 cell, adopts the IMDM nutrient solution containing 10% (v/v) foetal calf serum, 100U/ml penicillin and 100 μ g/ml Streptomycin sulphates, at 37 ℃, and 5% (v/v) CO
2cultivate.
(2) between CELL ELISA checking small peptide concentration dependent antagonism Fc γ RIIA-IgG, act on
96 orifice plate 2%(w/v) PBS-B(2%(w/v) PBS-B, is that the bovine serum albumin (BSA) with 2g is dissolved in 100ml PBS, all similar below) sealing, 4 ℃ are spent the night or room temperature 2h.The K562 cell 1%(w/v taking the logarithm vegetative period) PBS-B washes 3 times.1%(w/v) PBS-B resuspension K562 cell, adjusts concentration to 6 * 10
6/ ml, every hole adds K562 cell 100 μ l, removes supernatant after centrifugal.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.Small peptide group first adds small peptide, and concentration is for being respectively 10 μ g/ml, 100 μ g/ml, and incubated at room, after 30 minutes, adds identical IgG concentration gradient, hatches 60min for 37 ℃.With 1%(w/v) PBS-B washes 3 times, adds rabbit anti-human igg's antibody (Sigma) of horseradish peroxidase (HRP) mark, hatches 30min for 37 ℃.1%(w/v) PBS-B washes 3 times, with the colour developing of ABTS colouring reagents box (the raw work in Shanghai), the operation of concrete development step peace specification sheets.BioTek microplate reader 405nm wavelength reads 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.Take ordinate zou as 405nm place light absorption value, and X-coordinate is that the logarithmic value of IgG concentration is drawn, and the results are shown in Figure 1.From figure, can obviously find out, in IgG group, with the concentration increase of IgG, OD value obviously rises, and illustrates 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 OD value still increases along with increasing of IgG concentration, but compare with IgG group, under same concentrations, its OD value declines, and small peptide 100 μ g/ml groups than small peptide 10 μ g/ml group OD values declines obviously, illustrates 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.
Small peptide used: 1 ~ No. 6 small peptide.
(1) cell cultures
K562 cell, adopts the IMDM nutrient solution containing 10% (v/v) foetal calf serum, 100U/ml penicillin 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 test tube, then add the anti-sheep red blood cell (SRBC) antibody of rabbit of (1 ︰ 1000) dilution of equivalent, mix, put 15min in 37 ℃ of water-baths, with Hank ' s liquid washing 2 times, then with isopyknic Hank ' s liquid resuspension, be EA suspension.
(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, washes 3 times with HBSS, resuspension, and adjusting cell concn is 4 * 10
6cell/ml.
Positive group: get K562 cell suspension 0.1ml in EP pipe, add 0.1ml EA suspension, mix.
IgG group: get K562 cell suspension 0.1ml in EP pipe, first add human IgG 20 μ g, then add the EA suspension of 0.1ml, mix.
Small peptide group: get K562 cell suspension 0.1ml in EP pipe, first add patent to require 1 small peptide and patent to require 2 small peptide 20 μ g, then add the EA suspension of 0.1ml, mix.
4 ℃, 2h is standing, has hanged gently sedimentation cell, gets 20 μ l cell suspensions, uses cell counting count board smear, chooses at random a plurality of visuals field under microscope, and counting rosettes forms and inchoate K562 cell.
(4) rosettes forms experimental result
With 200 above K562 cells of cell counting count board counting, take on 1 K562 cell is rosettes positive cell in conjunction with 5 above sheep red blood cell (SRBC)s, and under microscope, Fig. 2 is shown in by photo.Counting rosettes positive cell accounts for the per-cent of total cell count, the results are shown in Figure 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 the sheep red blood cell (SRBC) of most of K562 Cell binding reduces compared with 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 IgG.
Claims (2)
1. a small peptide, is characterized in that, its aminoacid sequence is Glu-Pro-Ala-Pro-Ile-Phe.
2. the application of small peptide as claimed in claim 1 in preparation Fc γ IIA receptor antagonist.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002042772A1 (en) * | 2000-11-22 | 2002-05-30 | The University Of Pennsylvania | TRIPEPTIDE OF FCηRIIA |
| WO2008070927A1 (en) * | 2006-12-13 | 2008-06-19 | Suppremol Gmbh | Multimeric fc receptor polypeptides including a modified fc domain |
| CN101365799A (en) * | 2005-12-16 | 2009-02-11 | Lfb生物技术公司 | Method for preparing antibodies selective for activating Fc receptors |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6248332B1 (en) * | 1990-10-05 | 2001-06-19 | Medarex, Inc. | Targeted immunostimulation with bispecific reagents |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002042772A1 (en) * | 2000-11-22 | 2002-05-30 | The University Of Pennsylvania | TRIPEPTIDE OF FCηRIIA |
| CN101365799A (en) * | 2005-12-16 | 2009-02-11 | Lfb生物技术公司 | Method for preparing antibodies selective for activating Fc receptors |
| WO2008070927A1 (en) * | 2006-12-13 | 2008-06-19 | Suppremol Gmbh | Multimeric fc receptor polypeptides including a modified fc domain |
Non-Patent Citations (2)
| Title |
|---|
| Marino等.Prevention of systemic lupus erythematosus in MRL/lpr mice by administration of an immunoglobulin-binding peptide.《Nature Biotechnology》.2000,第18卷(第7期),735-739. |
| Prevention of systemic lupus erythematosus in MRL/lpr mice by administration of an immunoglobulin-binding peptide;Marino等;《Nature Biotechnology》;20000731;第18卷(第7期);735-739 * |
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