CN105111284A - Tumor necrosis factor inhibitory polypeptide and application thereof - Google Patents
Tumor necrosis factor inhibitory polypeptide and application thereof Download PDFInfo
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- CN105111284A CN105111284A CN201510563846.0A CN201510563846A CN105111284A CN 105111284 A CN105111284 A CN 105111284A CN 201510563846 A CN201510563846 A CN 201510563846A CN 105111284 A CN105111284 A CN 105111284A
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- polypeptide
- necrosis factor
- tumour necrosis
- rheumatoid arthritis
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Abstract
The invention relates to the field of drugs, particularly a polypeptide capable of inhibiting tumor necrosis factor and preventing and treating rheumatoid arthritis. The sequence is RINDISHTQSVSSKQKVTG and is a brand-new sequence. The polypeptide can be used for treating rheumatoid arthritis, and has potential new drug development value.
Description
Technical field:
The present invention relates to pharmaceutical field, the tumour necrosis factor be specifically related to for prevention and therapy or prevention rheumatoid arthritis suppresses polypeptide.
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.
TNF is a kind of cytokine of Lock-in in inflammation and immunne response.Research finds in the synovial fluid of RA patient, and TNF level raises, and plays an important role in pathological inflammatory and destruction of joint.The bio-pharmaceutical of current treatment rheumatoid arthritis has adalimumab, is the monoclonal antibody of TNF-α.Clinical study shows that adalimumab and methotrexate are share, and is used for the treatment of: to improving state of an illness antirheumatic (DMARDs), comprises the middle severe active rheumatoid arthritis patient that grows up of methotrexate unsatisfactory curative effect.Adalimumab and methotrexate drug combination, can slow down the progress (x-ray display) of patient articular's damage, and can improve physical function.Compared with traditional medicine, the curative effect of this kind of medicine is strong and lasting, can effectively alleviate disease symptoms, Advances in Imaging and functional level, and security is good, is applicable to various rheumatoid arthritis patients.But there is adalimumab to be macro-molecular protein.Long term injections is treated, and can cause allergic reaction on the one hand; On the other hand, in patient body, can lot of antibodies be produced, with the effect of adalimumab in meeting, cause failing to respond to any medical treatment.
Small protein or polypeptide are just not easy to bring out allergic immune reaction, and neutralization reaction.Therefore, small molecules TNF suppresses polypeptide just can address this problem.
Summary of the invention:
The present invention seeks to the feature for existing TNF antagonist, design the TNF polypeptide antagonist that a kind of molecular weight is little, can avoid producing antigen-reactive, be more applicable for clinical application.
Technical solution of the present invention is to provide a kind of tumour necrosis factor and suppresses polypeptide, and its sequence is RINDISHTQSVSSKQKVTG, and the application in treatment or prevention medicine for treating rheumatoid arthritis.By the treatment of multiple administering mode and prevention rheumatoid arthritis disease, comprise subcutaneous or intramuscular injection, intravenous injection or intravenous drip, oral administration as pill, capsule etc., nasal spray etc.
Beneficial outcomes:
Tumour necrosis factor in the present invention suppresses peptide sequence RINDISHTQSVSSKQKVTG, can targeted inhibition TNF, and the effect of the physiology that Tumor suppression mecrosis factor receptors produces or pathology, reaches the effect of prevention or treatment rheumatoid arthritis.
Through great many of experiments, contriver knows that tumour necrosis factor suppresses 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.Illustrate that tumour necrosis factor that the present invention designs suppresses polypeptide science, reasonable, feasible, effective, can as treatment or prevention medicine for treating rheumatoid arthritis.
Embodiment
Embodiment 1
Tumour necrosis factor suppresses polypeptide immanoprotection action in collagen-induced mouse arthritis animal model
Build collagen type mouse arthritis animal model, research tumour necrosis factor suppresses polypeptide 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.Respectively at the 40th day Joint scores after modeling, detect left and right metapedes ankle diameter respectively and observe medicine to the arthritic impact of mouse collagen type.
Tumour necrosis factor suppresses polypeptide immanoprotection action concrete outcome in collagen-induced mouse arthritis animal model as follows: tumour necrosis factor suppresses polypeptide on the impact of mouse collagen type arthritis knuckle swelling rate; positive controls, tumour necrosis factor suppress polypeptide high, medium and low dosage group Articular swelling rate to compare with model group, all have pole significant difference (P<0.01) experimental result to have statistical significance.Tumour necrosis factor suppresses polypeptide on the impact of mouse collagen type sacroiliitis foot pawl swelling rate, positive controls, tumour necrosis factor suppress polypeptide high, medium and low dosage group foot pawl swelling rate to compare 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 tumour necrosis factor suppresses polypeptide on the arthritic impact of collagen type (means ± SD)
* P<0.05; * P<0.01 (comparing with model group)
Conclusion: tumour necrosis factor suppresses polypeptide to have therapeutic action to mouse collagen type sacroiliitis.
Embodiment 2
Tumour necrosis factor suppresses polypeptide 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, tumour necrosis factor suppresses low middle high 3 the dosage groups (0.2 of 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 0.1ml 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.Respectively at the 21st day Joint scores after modeling, detect left and right metapedes ankle diameter respectively and observe medicine to the arthritic impact of rat adjuvant type.
Polypeptide is immanoprotection action in adjuvanticity rat arthritis animal model, concrete outcome is as follows: tumour necrosis factor suppresses polypeptide on the impact of the left back ankle diameter of rat primary sacroiliitis, rat positive controls, tumour necrosis factor suppress the left back ankle diameter of basic, normal, high dosage group of polypeptide to compare with model group, have pole significant difference (P<0.01); Tumour necrosis factor suppresses polypeptide on the impact of the right back ankle diameter of rat post-traumatic arthritis, rat positive controls, tumour necrosis factor suppress the right back ankle diameter of polypeptide basic, normal, high dosage group to compare with model group, have significant difference (P<0.05).Tumour necrosis factor suppresses polypeptide on the impact of adjuvant type rats with arthritis Joint scores, the scoring of polypeptide basic, normal, high dosage group four limbs, significantly lower than model control group (P < 0.05), all has statistical significance with model control group comparing difference.
Table 2 tumour necrosis factor suppresses polypeptide on the arthritic impact of adjuvant type (means ± SD)
* P<0.05; * P<0.01 (comparing with model group)
Conclusion: tumour necrosis factor suppresses polypeptide to have therapeutic action to AA rat arthritis.
SEQUENCELISTING
Pu Luoda bio tech ltd, <110> Suzhou
<120> tumour necrosis factor suppresses polypeptide and application thereof
<130>
<160>1
<170>PatentInversion3.5
<210>1
<211>19
<212>PRT
<213> artificial sequence
<400>1
ArgIleAsnAspIleSerHisThrGlnSerValSerSerLysGlnLys
151015
ValThrGly
Claims (3)
1. tumour necrosis factor suppresses polypeptide, it is characterized in that its sequence is RINDISHTQSVSSKQKVTG.
2. the application of suppression polypeptide in treatment and prevention rheumatoid arthritis disease of claim 1.
3. according to the purposes of the arbitrary described suppression polypeptide of claim 1-2, 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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| Application Number | Priority Date | Filing Date | Title |
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| CN201510563846.0A CN105111284A (en) | 2015-09-08 | 2015-09-08 | Tumor necrosis factor inhibitory polypeptide and application thereof |
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| CN201510563846.0A CN105111284A (en) | 2015-09-08 | 2015-09-08 | Tumor necrosis factor inhibitory polypeptide and application thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103254291A (en) * | 2013-05-30 | 2013-08-21 | 苏州普罗达生物科技有限公司 | Tumor necrosis factor-alpha polypeptide inhibitors and application thereof |
| CN103265619A (en) * | 2013-05-30 | 2013-08-28 | 苏州普罗达生物科技有限公司 | Tumor necrosis factor-alpha polypeptide inhibitor and application thereof |
| CN103285373A (en) * | 2013-05-30 | 2013-09-11 | 苏州普罗达生物科技有限公司 | Preparation method and application of tumor necrosis factor (TNF)-alpha polypeptide inhibitor |
| CN103739670A (en) * | 2013-12-31 | 2014-04-23 | 罗瑞雪 | Polyethylene glycol modified polypeptide for inhibiting tumor necrosis factor-alpha and application of polypeptide |
-
2015
- 2015-09-08 CN CN201510563846.0A patent/CN105111284A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103254291A (en) * | 2013-05-30 | 2013-08-21 | 苏州普罗达生物科技有限公司 | Tumor necrosis factor-alpha polypeptide inhibitors and application thereof |
| CN103265619A (en) * | 2013-05-30 | 2013-08-28 | 苏州普罗达生物科技有限公司 | Tumor necrosis factor-alpha polypeptide inhibitor and application thereof |
| CN103285373A (en) * | 2013-05-30 | 2013-09-11 | 苏州普罗达生物科技有限公司 | Preparation method and application of tumor necrosis factor (TNF)-alpha polypeptide inhibitor |
| CN103739670A (en) * | 2013-12-31 | 2014-04-23 | 罗瑞雪 | Polyethylene glycol modified polypeptide for inhibiting tumor necrosis factor-alpha and application of polypeptide |
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