CN105504022A - NF-kappa B polypeptide and application thereof - Google Patents

Abstract

The invention relates to the field of medicines, particularly to a polypeptide which has inhibiting NF-kappa B and can prevent and treat rheumatoid arthritis. The sequence of the polypeptide is RGDTRILAQHRLYYYNSQSE which is a brand-new sequence. The polypeptide has the benefit of treating rheumatoid arthritis, and has the potential new drug development value.

Description

Nuclear Factor-Kappa B polypeptide and application thereof

Technical field:

The present invention relates to pharmaceutical field, be specifically related to the nuclear Factor-Kappa B peptide inhibitor 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, immunosuppressor: conventional have Rheumatrex, endoxan, azathioprine, trypterygine, Stem of Orientoine etc.

Nuclear Factor-Kappa B is that one is extensively present in intracellular nuclear factor, and with the generation of inflammation in sacroiliitis, cartilage injury, the formation of cell migration and pannus has important relation.Take nuclear Factor-Kappa B as action target spot, the new way of the diseases such as treatment of arthritis may be become.Non-steroidal anti-inflammatory drugs, glucocorticosteroid, glycosaminoglycan and Novel protease body inhibitor etc. find the activation that all can suppress nuclear Factor-Kappa B.In addition, nuclear Factor-Kappa B decoy ODN and siRNA interference treatment also achieve gratifying achievements.However, the nuclear Factor-Kappa B peptide inhibitor 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 nuclear Factor-Kappa B antagonist, design the nuclear Factor-Kappa B 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 nuclear Factor-Kappa B peptide inhibitor, and its sequence is RGDTRILAQHRLYYYNSQSE, and the application in treatment or prevention medicine for treating rheumatoid arthritis.

Beneficial outcomes:

Nuclear Factor-Kappa B peptide sequence RGDTRILAQHRLYYYNSQSE in the present invention, can targeted inhibition nf-KB, and the physiology suppressing nuclear Factor-Kappa B acceptor to produce or the effect of pathology, reach the effect of prevention or treatment rheumatoid arthritis.

Through great many of experiments, contriver knows that nuclear Factor-Kappa B peptide inhibitor 3 can suppress adjuvant type rat kind rheumatic arthritis, experiment in vivo proves to have the arthritic effect of significant treatment similar rheumatism type, and few side effects, the few cost of consumption reduces.Illustrate that the nuclear Factor-Kappa B peptide inhibitor 3 that the present invention designs is scientific, rational, feasible and effective, can as treatment or prevention medicine for treating rheumatoid arthritis.

Embodiment

Described polypeptide is synthesized by Shanghai gill.

Embodiment 1

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 90 (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 9 groups at random, Normal group respectively, model control group, low middle high 3 the dosage groups (0.1 of polypeptide, 0.2,0.4mg/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: polypeptide 3 dosage groups (0.1,0.2,0.4mg/kg): 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 after modeling the 8th, 11,14,17,20,23 and 26 days, Joint scores, detect left and right metapedes ankle diameter respectively and observe medicine to the arthritic impact of rat adjuvant type.Arthritis evaluations index is as follows:

1) Joint scores

Four limbs: by 0-4 Pyatyi scorings: 0=is without erythema or redness; The erythema that 1=is slight or swelling, one of them front/rear toe joint has erythema or swelling; Erythema or swelling is there is in 2=more than a toe; Sufficient pawl swelling under 3=ankle or wrist joint; 4=comprises the whole sufficient pawl swelling of ankle joint.Rat four foots are marked respectively, and most higher assessment is divided into 16 points.

Carry out Joint scores respectively at after modeling 8,11,14,17,20,23 and 26 days, and record result.

2) ankle diameter is measured

Respectively at before modeling and after modeling 8,11,14,17,20,23 and 26 days with inside the left and right ankle of vernier caliper measurement rat to the diameter in outside and ankle thickness, and record result.

The measurement data of test-results is added and subtracted standard deviation (mean ± SD) with mathematical mean and is represented, carry out carrying out t inspection between each administration group and control group with SPSS11.0 software, in table, * represents p<0.05, and * * represents p<0.01.

Result: after modeling, rat is compared with normal rat, the left back foot of rat waste time place's injection containing the mycobacterium tuberculosis complete Freund's adjuvant of deactivation after, left back foot can produce primary arthritis rapidly, occurs obvious swelling, and with festering; Start to occur post-traumatic arthritis after the about 10d of right back foot, the score value of scoring increases gradually; Ear's blood vessel hyperplasia is obvious simultaneously, obviously red and swollen; There is swelling in caudal articular process.Polypeptide immanoprotection action in collagen-induced rat arthritis animal model the results are shown in Table 2, and as seen from table, polypeptide can play immanoprotection action in body at collagen-induced rat arthritis animal model, and concrete outcome is as follows:

Polypeptide is on the impact of the left whole pawl swelling of rat primary sacroiliitis, and in rat positive controls, polypeptide, the left back ankle diameter of dosage group compares with model group, has pole significant difference (p<0.01); AP25 is low, the left back ankle diameter of high dose group compares with model group, and all have significant difference (p<0.05), experimental result has statistical significance.Polypeptide is on the impact of the right whole pawl swelling of rat post-traumatic arthritis, and the right back ankle diameter of rat positive controls, polypeptide basic, normal, high dosage group compares with model group, has significant difference (p<0.05).Polypeptide is on the impact of adjuvant type rats with arthritis clinical score, and 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 1 polypeptide is to immanoprotection action in adjuvant type class rat arthritis animal model

* represent p<0.05, * * represents p<0.01.

Conclusion: polypeptide has therapeutic action to AA rat arthritis.

SEQUENCELISTING

Pu Luoda bio tech ltd, <110> Suzhou

<120> nuclear Factor-Kappa B polypeptide and application thereof

<130>

<160>1

<170>PatentInversion3.3

<210>1

<211>20

<212>PRT

<213> artificial sequence

<400>1

ArgGlyAspThrArgIleLeuAlaGlnHisArgLeuTyrTyrTyrAsn

151015

SerGlnSerGlu

20

Claims (2)

1. nuclear Factor-Kappa B polypeptide, is characterized in that its sequence is RGDTRILAQHRLYYYNSQSE.

2. nuclear Factor-Kappa B polypeptide, the application in treatment or prevention medicine for treating rheumatoid arthritis.