CN105061583A - Peripheral interleukin 35 polypeptide and application thereof - Google Patents
Peripheral interleukin 35 polypeptide and application thereof Download PDFInfo
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- CN105061583A CN105061583A CN201510556864.6A CN201510556864A CN105061583A CN 105061583 A CN105061583 A CN 105061583A CN 201510556864 A CN201510556864 A CN 201510556864A CN 105061583 A CN105061583 A CN 105061583A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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Abstract
The invention relates to the field of medicines and in particular relates to a peripheral interleukin 35 polypeptide which can be used for preventing and treating rheumatoid arthritis. The sequence of the polypeptide is EAARTCSRLLTPSIHLISGAHVV and is brand-new. The polypeptide has the beneficial effects that the polypeptide can be used for treating rheumatoid arthritis and has potential new medicine development value.
Description
Technical field:
The present invention relates to pharmaceutical field, be specifically related to the polypeptide for prevention and therapy or prevention rheumatoid arthritis.
Background technology:
Rheumatoid arthritis (rheumatoidarthritis, RA) is one of clinical modal inflammatory arthropathy and main disability-causing factor.Be about 0.5%-1.0% in the whole world, the morbidity of RA is about 0.4% in China.RA can betide any age, and with advancing age, sickness rate also increases thereupon.Women the age occurred frequently be 45-55 year, sex and RA onset relation are close, and the ratio of men and women is about 1:3.RA is the chronic systemic inflammation disease that a kind of cause of disease not yet understands, for main clinical manifestation, belongs to autoimmune inflammatory disease with pathology outside chronic, symmetry, many synovial joints inflammation and joint.Patient often with hand or wrist pain and swelling (particularly the swelling at wrist back), for onset symptoms, do not alleviate by Symptoms last, though common symptomatic treatment can relief of symptoms, usually because medication is irregular or in shortage and cause symptom repeatedly.Can occur during disease progression that obvious morning stiff, usually can reach more than 1 hour, and constantly increase the weight of; There is certain joint function disturbance simultaneously.
The cause of disease of rheumatoid arthritis and pathogenesis are not yet completely clear, and its basic pathology feature is vasculitis and synovitis.Intraarticular synovial membrane blood vessel hyperplasia, forms pannus, causes synovial membrane to thicken, ooze out and increase, and secretion cytokine profiles, invades cartilage and cause bone damage.All erodables are organized also to the flesh chamber around it, ligament, stndon sheath and muscle etc., thus affects the stable of joint, easily joint deformity occur and occur dysfunction.Vasculitis also can invade each organs and tissues in the whole body, forms systemic disease.
The medicine of current treatment RA is divided into two large classes: control symptom medicine and control disease medicine.Due to RA etiology unknown, therefore there is no the medicine that can be rated as and control disease now.The antirheumatic controlling symptom is divided into four classes: one, non-steroidal anti-inflammatory drugs, and be commonly referred to a line medicine, this kind of medicament categories is various, nearly tens of kinds, domestic market.Two, steroid hormone, hormone is an extraordinary pain stop and anti-inflammation medicine, but is used alone for a long time and can not improves the state of an illness, bring many side effects on the contrary, transitionality before hormone does medication onset slowly as two wires is with being fine, but consumption is little, and the time is unsuitable long.Heavier in the state of an illness, with the patient of extra-articular manifestation, short impacts, and necessary when combining two wires medicine treatment.Three, act on antirheumatic slowly, be commonly referred to two wires medicine, so-called slow effect cartridge bag draws together antimalarial drug, golden salt, Trolovol and willow nitrogen sulfapyridine, and their treatment RA onsets are slow, and long term has certain mitigation to the RA state of an illness, therefore feelings of also pretending illness improve medicine.Four, immune peptide: conventional have Rheumatrex, endoxan, azathioprine, trypterygine, Stem of Orientoine etc.Therefore, safer, the effective novel resisting rheumatoid disease arthritis drug of exploitation is badly in need of.
Interleukin-3 5 (IL-35) is the anti-inflammatory cytokines found recently, can react by immunity moderation, thus stops and delay generation and the development of immunological disease.Research shows, in human body, its major part is secreted by regulatory T cells, and is the necessary key cytokines of this cells play immunoregulation effect.Research finds, IL-35 and arthritic closely related.Cytokine is immunomodulatory person, and the cytokine around in Lymphoid tissue and target organ plays strong influence in the trigger autoimmune arthritic initial period.To the individuality of sensitivity, it can push away the destruction in diarthrodial inflammation and joint.IL-35 has Immunosuppression function, effectively inflammation-inhibiting cytokine and T effector cell can secrete, stop TH17 cytodifferentiation, suppresses its function, affect IL-17 level and function.Niedbala etc. set up collagen-induced mouse arthritis (CIA) model with DBA/1 mouse, after finding injection IL-35, the incidence of mouse arthritis and quantity significantly reduce, clinical symptom is improved, tissue pathologies change alleviates, this discovery shows, IL-35 is a potential therapeutic goal of rheumatoid arthritis.However, periphery interleukin-13 5 polypeptide of unripe exploitation comes out, and is used for the treatment of RA.
Summary of the invention:
The present invention seeks to the feature for existing resisting rheumatoid disease arthritis drug, design a kind of micromolecular periphery interleukin-13 5 polypeptide, be applicable to the application of clinical treatment rheumatoid arthritis.
Technical solution of the present invention is to provide a kind of periphery interleukin-13 5 polypeptide, and its sequence is EAARTCSRLLTPSIHLISGAHVV, and the application in treatment or prevention medicine for treating rheumatoid arthritis.
Beneficial outcomes:
Periphery interleukin-13 5 peptide sequence EAARTCSRLLTPSIHLISGAHVV in the present invention, can play the effect of interleukin-13 5, the physiology produced with interleukin-13 5 acceptor or the effect of pathology, reaches the effect of prevention or treatment rheumatoid arthritis.
Through great many of experiments, contriver knows that periphery interleukin-13 5 polypeptide can suppress the development of adjuvant type rat kind rheumatic arthritis and DBA/1 mouse collagen type rheumatoid arthritis, experiment in vivo proves to have the arthritic effect of significant treatment similar rheumatism type.Periphery interleukin-13 5 polypeptide science that the present invention designs, reasonable, feasible, effective is described, can as treatment or prevention medicine for treating rheumatoid arthritis.
Embodiment
Polypeptide of the present invention is synthesized by Shanghai gill.
Embodiment 1
Periphery interleukin-13 5 polypeptide is immanoprotection action in collagen-induced mouse arthritis animal model
Build collagen type mouse arthritis animal model, research periphery interleukin-13 5 polypeptide is to the therapeutic action of mouse collagen Induced Arthritis (collageninducedarthritis, CIA).Adopt mouse as animal subject, SPF level DBA/1 mouse 60 (is provided by Shanghai western pul-Bi Kai laboratory animal company limited (Sino-BritishSIPPRLab.AnimalLtd), animal productiong ticket number: SCXK (Shanghai) 2008-0016), male, 7-8 week age, body weight is 18-22g, be divided into 6 groups at random, Normal group respectively, model control group, low middle high 3 the dosage groups (0.4,0.8,1.6mg/kg) of polypeptide and positive drug control group (methotrexate 2mg/kg).Except normal group, within the 0th day, each experimental group sets up mouse CIA model, and method is chicken cartilage II Collagen Type VI (c II) becomes 4mg/ml solution with 0.1mol/l acetate dissolution, in 4 DEG C of refrigerator overnight.Experimental day is fully emulsified with complete Freund's adjuvant (CFA) equal-volume containing 4mg/mlMyeobaeteriumtuberculosisstrainH37Rv with II Collagen Type VI, after DBA/1 mouse anesthesia, often only inject emulsifying agent 50 μ l in its afterbody intracutaneous and carry out sensitization, after fully emulsified with II Collagen Type VI (c II) of 4mg/ml and incomplete Freund's adjuvant (IFA) equal-volume after 21d, carry out immunity again with the emulsifying agent of same dose in afterbody.Modeling 30d plays subcutaneous administrations: 3 dosage groups (0.4,0.8,1.6mg/kg) of polypeptide: every day twice, continuous 10 days; Positive drug control group (methotrexate 2mg/kg): every five days once, continuous 3 times; Normal group and model control group (physiological saline): continuous 10 days.Medicine is observed on the arthritic impact of mouse collagen type respectively at the 40th day Joint scores, detection left and right metapedes ankle diameter after modeling.
Periphery interleukin-13 5 polypeptide immanoprotection action concrete outcome in collagen-induced mouse arthritis animal model is as follows: periphery interleukin-13 5 polypeptide is on the impact of mouse collagen type arthritis knuckle swelling; positive controls, periphery interleukin-13 5 polypeptide high, medium and low dosage group Articular swelling compare with model group, all have pole significant difference (P<0.01) experimental result to have statistical significance.Periphery interleukin-13 5 polypeptide is on the impact of mouse collagen type sacroiliitis foot pawl swelling, positive controls, periphery interleukin-13 5 polypeptide high, medium and low dosage group foot pawl swelling compares with model group, all have pole significant difference (P<0.01), experimental result has statistical significance.Polypeptide is on the impact of collagen type arthritic mice Joint scores, the scoring of polypeptide basic, normal, high dosage group four limbs is significantly lower than model control group (P < 0.01), compare pole significant difference with model control group, experimental result has statistical significance.
Table 1 periphery interleukin-13 5 polypeptide is on the arthritic impact of collagen type (means ± SD)
* P<0.05; * P<0.01 (comparing with model group)
Conclusion: periphery interleukin-13 5 polypeptide has therapeutic action to mouse collagen type sacroiliitis.
Embodiment 2
Periphery interleukin-13 5 polypeptide is to immanoprotection action in adjuvant type rat arthritis animal model
Build adjuvant type rat arthritis animal model, research polypeptide is to the therapeutic action of adjuvant-induced arthritis (Adjuvantarthritis, AA) rat.Adopt rat as animal subject, SPF level SD rat 60 (is provided by Shanghai western pul-Bi Kai laboratory animal company limited (Sino-BritishSIPPRLab.AnimalLtd), animal productiong ticket number: SCXK (Shanghai) 2008-0016), male, body weight is 140g-160g, be divided into 6 groups at random, Normal group respectively, model control group, low middle high 3 the dosage groups (0.2 of periphery interleukin-13 5 polypeptide, 0.4,0.8mg/kg) and positive drug control group (methotrexate 1mg/kg).Except normal group, within the 0th day, each experimental group sets up rat AA model, and method is that injection of wasting time fully afterwards in the left side of rat causes experimental animal model of CFA induced adjuvant arthritis in rats containing mycobacterium tuberculosis (H37RA, 10mg/ml) the complete Freund's adjuvant 0.08ml of deactivation.Modeling plays subcutaneous administrations on the 10th day: 3 dosage groups (0.2,0.4,0.8mg/kg) of polypeptide: every day twice, continuous 10 days; Positive drug control group (methotrexate 1mg/kg): every five days once, continuous 3 times; Normal group and model control group (physiological saline): continuous 10 days.Medicine is observed on the arthritic impact of rat adjuvant type respectively at the 21st day Joint scores, detection left and right metapedes ankle diameter after modeling.
Polypeptide is immanoprotection action in adjuvanticity rat arthritis animal model, concrete outcome is as follows: periphery interleukin-13 5 polypeptide is on the impact of the left back ankle diameter of rat primary sacroiliitis, the left back ankle diameter of basic, normal, high dosage group of rat positive controls, periphery interleukin-13 5 polypeptide compares with model group, has pole significant difference (P<0.01); Periphery interleukin-13 5 polypeptide is on the impact of the right back ankle diameter of rat post-traumatic arthritis, rat positive controls, the right back ankle diameter of periphery interleukin-13 5 polypeptide basic, normal, high dosage group compare with model group, have significant difference (P<0.05).Periphery interleukin-13 5 polypeptide is on the impact of adjuvant type rats with arthritis Joint scores, the scoring of polypeptide basic, normal, high dosage group extremities joint, significantly lower than model control group (P < 0.05), all has statistical significance with model control group comparing difference.
Table 2 periphery interleukin-13 5 polypeptide is on the arthritic impact of adjuvant type (means ± SD)
* P<0.05; * P<0.01 (comparing with model group)
Conclusion: periphery interleukin-13 5 polypeptide has therapeutic action to AA rat arthritis.
SEQUENCELISTING
Pu Luoda bio tech ltd, <110> Suzhou
<120> periphery interleukin-13 5 polypeptide and application thereof
<130>
<160>1
<170>PatentInversion3.5
<210>1
<211>23
<212>PRT
<213> artificial sequence
<400>1
GluAlaAlaArgThrCysSerArgLeuLeuThrProSerIleHisLeu
151015
IleSerGlyAlaHisValVal
20
Claims (3)
1. periphery interleukin-13 5 polypeptide, is characterized in that its sequence is EAARTCSRLLTPSIHLISGAHVV.
2. the application of polypeptide in treatment and prevention rheumatoid arthritis disease of claim 1.
3. according to the purposes of the arbitrary described polypeptide of claim 2, it is characterized in that: by multiple administering mode treatment and prevention rheumatoid arthritis disease, comprise subcutaneous or intramuscular injection, intravenous injection or intravenous drip, oral administration as pill, capsule etc., nasal spray etc.
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| CN201510556864.6A CN105061583A (en) | 2015-09-05 | 2015-09-05 | Peripheral interleukin 35 polypeptide and application thereof |
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| CN201510556864.6A CN105061583A (en) | 2015-09-05 | 2015-09-05 | Peripheral interleukin 35 polypeptide and application thereof |
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| CN105061583A true CN105061583A (en) | 2015-11-18 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105688190A (en) * | 2016-01-27 | 2016-06-22 | 武汉大学 | Application of IL (Interleukin)-35 in preparation of antiviral drug |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102307586A (en) * | 2008-12-22 | 2012-01-04 | 都柏林伊丽莎白女皇神学院院长、研究员及专家协会 | Compounds and methods for the treatment of autoimmune and inflammatory disease |
| CN103739669A (en) * | 2013-12-31 | 2014-04-23 | 罗瑞雪 | Polypeptide capable of inhibiting interleukin-6 and application thereof |
| CN104127859A (en) * | 2011-12-27 | 2014-11-05 | 中国药科大学 | Application of polypeptides in preparation of medicament for treating or preventing rheumatoid arthritis |
-
2015
- 2015-09-05 CN CN201510556864.6A patent/CN105061583A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102307586A (en) * | 2008-12-22 | 2012-01-04 | 都柏林伊丽莎白女皇神学院院长、研究员及专家协会 | Compounds and methods for the treatment of autoimmune and inflammatory disease |
| CN104127859A (en) * | 2011-12-27 | 2014-11-05 | 中国药科大学 | Application of polypeptides in preparation of medicament for treating or preventing rheumatoid arthritis |
| CN103739669A (en) * | 2013-12-31 | 2014-04-23 | 罗瑞雪 | Polypeptide capable of inhibiting interleukin-6 and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| ZHANG G等: "登录号： ELW68647.1", 《GENBANK》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105688190A (en) * | 2016-01-27 | 2016-06-22 | 武汉大学 | Application of IL (Interleukin)-35 in preparation of antiviral drug |
| CN105688190B (en) * | 2016-01-27 | 2020-03-10 | 武汉大学 | Application of interleukin 35 in preparation of antiviral drugs |
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Application publication date: 20151118 |