CN103254292A - Tyrosine kinase tyrosine polypeptideinhibitor of vascular endothelial growth factor receptor 2 and application thereof - Google Patents
Tyrosine kinase tyrosine polypeptideinhibitor of vascular endothelial growth factor receptor 2 and application thereof Download PDFInfo
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- CN103254292A CN103254292A CN 201310209093 CN201310209093A CN103254292A CN 103254292 A CN103254292 A CN 103254292A CN 201310209093 CN201310209093 CN 201310209093 CN 201310209093 A CN201310209093 A CN 201310209093A CN 103254292 A CN103254292 A CN 103254292A
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Abstract
The invention relates to a tyrosine kinase tyrosine polypeptide inhibitor of a vascular endothelial growth factor receptor 2 and an application thereof. The invention relates to field of medicines, and in particular relates to polypeptide which can inhibit tyrosine kinase of the vascular endothelial growth factor receptor 2 and prevent and treat rheumatoid arthritis. The sequence of the polypeptide is a novel sequence: Val-Gys-Cys-Ser-Thr-Arg-Glu. The inhibitor provided by the invention has the beneficial effects that the inhibitor can be used for treating rheumatoid arthritis and has potential novel medicine development value.
Description
Technical field:
The present invention relates to pharmaceutical field, be specifically related to the vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors for prevention and treatment rheumatoid arthritis.
Background technology:
(rheumatoid arthritis RA) is one of clinical modal inflammatory arthropathy and main disability-causing factor to rheumatoid arthritis.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.The women is 45-55 year at the age occurred frequently, and sex and RA onset relation are close, the men and women than about 1:3.
New vessel generates, and under normal physiological conditions, is subjected to altitude mixture control, and process is absolutely necessary in reproduction, fetal development, tissue repair and wound healing.Vasculogenesis also takes place under multiple pathological conditions, for example RA.In the pathologic process of RA, angiogenesis is a kind of significant Histological change, and new vessel forms and follows synovial hyperplasia and cell infiltration, is the basis of the formation of RA medium vessels screen and destruction of joint.Originally should not have the joint cartilage of blood vessel existence because of certain ANOMALOUS VARIATIONS, and formed new blood vessel, and made cartilage suffer erosion, caused joint deformity or pain.New vessel causes that ANOMALOUS VARIATIONS takes place in rheumatoid arthritis patients synovial tissue, and normal people's synovium of joint internal layer only 1-2 confluent monolayer cells is formed, and RA patient's synovial membrane internal layer has 4-10 confluent monolayer cells (sometimes even above 20 layers) usually.These cells not only quantitatively increase unusually, and are in the state of Showed Very Brisk in function, and they can secrete a large amount of cytokines, signaling molecule and proteolytic enzyme, accelerate the process of destruction of joint.
Vascular endothelial growth factor receptor 2(VEGFR2) also claims to contain the acceptor (KDR) that kinases inserts the territory, belong to the receptor tyrosine kinase superfamily.VEGFR2 plays significant feature in the new vessel generative process.Complicated cascade and extracellular matrix components and the soluble factor interaction of biochemical signals take place by the surperficial VEGFR2 activation of irritation cell endotheliocyte in its part VEGF, cause lumen to form and be divided into the blood vessel of maturation.In addition, the cell that these are activated is through the cell proliferation process, and the expression that improves cell adhesion molecule increases the secretion of proteolytic ferment, increases cell migration and invasion and attack.
At present, the inhibitor of target KDR has become the research focus of the emerging anti-angiogenic drugs of exploitation.However, the vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors of ripe exploitation do not come out, and are used for the treatment of RA.
Summary of the invention:
The present invention seeks to be used for the treatment of RA at a kind of vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors of design.
Technical solution of the present invention provides a kind of vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors 1, and its sequence is Val-Cys-Cys-Ser-Thr-Arg-Glu, and the application in preparation treatment medicine for treating rheumatoid arthritis.
Principle of the present invention is that vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors are combined with VEGFR2, suppress the effect that VEGFR2 produces physiology or pathology, play the inhibition vascular endothelial cell proliferation, migration, the lumen of vessels pipe forms, and the relevant cell factor secretion, thereby play the effect for the treatment of rheumatoid arthritis.
Useful result:
Vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors 1 sequence Val-Cys-Cys-Ser-Thr – Arg-Glu among the present invention, can suppress vascular endothelial growth factor receptor 2 Tyrosylprotein kinases by target, suppress the physiology of VEGFR2 generation or the effect of pathology, reach the effect for the treatment of rheumatoid arthritis.
The contriver knows that through a large amount of experiments vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors 1 can suppress the development of adjuvant type rat kind rheumatic arthritis and DBA/1 mouse collagen type rheumatoid arthritis, experimental results show that to have the arthritic effect of significant treatment similar rheumatism type in the body, and few side effects.Illustrate the present invention design vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors 1 science, reasonable, feasible effectively, can be as the treatment medicine for treating rheumatoid arthritis.
Description of drawings
Accompanying drawing 1 peptide inhibitor molecular configurations synoptic diagram.1.Val Xie Ansuan, 2.Cys halfcystine, 3.Cys halfcystine, 4.Ser Serine, 5.Thr Threonine, 6.Arg arginine, 7.Glu L-glutamic acid.
Embodiment
Embodiment 1
The chemical synthesis process of polypeptide
Polypeptide is synthetic with the Fmoc chemical process.Building-up reactions is carried out to the N end from the C end, and Rink medium (can buy in Advanced ChemTech company) has free amino group, the Glu that is linked in sequence, Arg, Thr, Ser, Cys, Cys and Val.In each step connection procedure, amino-acid residue all will activate, and the HBTU of 4 times of free amino groups on medium is arranged in the activator mixture, HOBt, DIEA and Fmoc-amino acid.After each amino acid whose ligation, all use the mixture of a pyridine/acetic acid/N-Methylimidazole (4:1:0.5) to seal the free amino group that does not connect, capping 10 min.After each amino acid whose ligation, next amino acid all will remove the Fmoc-group on the medium before connecting, and goes the Fmoc-group to use the dimethyl formamide that contains 20% piperidines, needs 15 minutes.At last, after all amino-acid residues were linked in sequence, polypeptide cut down from medium with 98% trifluoroacetic acid, and cutting was at room temperature carried out 2 hours.
Use above-mentioned electrochemical conditions and can synthesize and obtain polypeptide, sequence is Val-Cys-Cys-Ser-Thr-Arg-Glu, and this sequence is brand-new sequence.
Embodiment 2
Vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors 1 immanoprotection action in collagen-induced mouse arthritis animal model
Make up collagen type mouse arthritis animal model, 1 pair of collagen-induced property of mouse of research vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors sacroiliitis (collagen induced arthritis, therapeutic action CIA).Adopt mouse as animal subject, 90 of SPF level DBA/1 mouse (are provided by west, Shanghai pul-Bi Kai laboratory animal company limited (Sino-British SIPPR Lab. Animal Ltd), animal production licence number: SCXK (Shanghai) 2008-0016), male, age in 7-8 week, body weight is 18-22 g, be divided into 6 groups at random, it is respectively the normal control group, model control group, high 3 dosage groups (0.4,0.8,1.6 mg/kg) and positive drug control group (methotrexate 2 mg/kg) during peptide inhibitor 1 hangs down.Except normal group, each experimental group was set up mouse CIA model in the 0th day, and to be chicken cartilage II Collagen Type VI (c II) become the solution of 4 mg/ml with 0.1 mol/l acetate dissolution to method, in 4 ℃ of refrigerator overnight.Experiment was fully emulsified with complete Freund's adjuvant (CFA) equal-volume that contains 4 mg/ml Myeobaeterium tuberculosis strain H37Rv with the II Collagen Type VI same day, after treating the DBA/1 mouse anesthesia, 50 μ l carry out sensitization in every injection of its afterbody intracutaneous emulsifying agent, and the II Collagen Type VI (c II) with 4 mg/ml behind 21 d carries out immunity again with the fully emulsified back emulsifying agent with same dose of incomplete Freund's adjuvant (IFA) equal-volume in afterbody.Drug administration by injection under modeling the 30th d peeling: 3 dosage groups of polypeptide 4 (0.4,0.8,1.6 mg/kg): every day twice, continuous 10 days; Positive drug control group (methotrexate 2 mg/kg): per five days once, continuous 3 times; Normal control group and model control group (physiological saline): continuous 10 days.Respectively at weighing in the 21st day to the 70th day per 3 days after the modeling, the joint scoring, detecting left and right sides metapedes ankle diameter respectively and observe medicine to the arthritic influence of mouse collagen type.
The result: mouse is compared with normal mouse after the modeling, immunity back the 27th day, and CIA mouse foot pawl redness, the arthritis index scoring is increased, and model group 45-60 days was the swelling peak, and model group increases hardly from the 35th day beginning body weight, and the later stage also has decline slightly.Vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors 1 immanoprotection action concrete outcome in collagen-induced mouse arthritis animal model is as follows:
The influence of the whole pawl swelling degree in 1 pair of mouse collagen type of vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors sacroiliitis left side, positive controls, the vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitor left back ankle diameters of 1 high, medium and low dosage group and model group relatively all have utmost point significant difference (P＜0.01) experimental result to have statistical significance.The influence of the right whole pawl swelling degree of 1 pair of mouse collagen type of vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors sacroiliitis, positive controls, the vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitor right back ankle diameters of 1 high, medium and low dosage group and model group are relatively, utmost point significant difference (P＜0.01) is all arranged, and experimental result has statistical significance.The influence of 1 pair of collagen type sacroiliitis of vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors mouse clinical score, polypeptide 4 basic, normal, high dosage group four limbs scorings significantly are lower than model control group (P＜0.01), compare utmost point significant difference with model control group, experimental result has statistical significance.The influence of 1 pair of collagen type sacroiliitis of vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors mouse body weight, polypeptide 4 high, medium and low dosage group body weight are significantly higher than model control group (P＜0.01), compare utmost point significant difference with model control group, experimental result has statistical significance.
Conclusion: 1 pair of mouse collagen type of vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors sacroiliitis has therapeutic action.
Embodiment 3
Immanoprotection action in 1 pair of adjuvant type of vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors rat arthritis animal model
Make up adjuvant type rat arthritis animal model, 1 pair of adjuvant-induced arthritis of research vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors (Adjuvant arthritis, AA) therapeutic action of rat.Adopt rat as animal subject, 90 of SPF level SD rats (are provided by west, Shanghai pul-Bi Kai laboratory animal company limited (Sino-British SIPPR Lab. Animal Ltd), animal production licence number: SCXK (Shanghai) 2008-0016), male, body weight is 140 g-160 g, be divided into 6 groups at random, it is respectively the normal control group, model control group, high 3 dosage groups (0.2 during vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors 1 hang down, 0.4,0.8 mg/kg) and positive drug control group (methotrexate 1 mg/kg).Except normal group, each experimental group was set up rat AA model in the 0th day, and method is that mycobacterium tuberculosis (H37RA, 10 mg/ml) complete Freund's adjuvant 0.08 ml that injection contains deactivation that wastes time fully behind the left side of rat causes the rat assist agent arthritis model.Drug administration by injection under the 10th day peeling of modeling: 3 dosage groups of polypeptide 4 (0.2,0.4,0.8 mg/kg): every day twice, continuous 10 days; Positive drug control group (methotrexate 1 mg/kg): per five days once, continuous 3 times; Normal control group and model control group (physiological saline): continuous 10 days.Respectively at after the modeling the 8th, 11,14,17,20,23 and 26 days, weigh in, the joint scoring, detect left and right sides metapedes ankle diameter respectively and observe medicine to the arthritic influence of rat adjuvant type.
The result: rat is compared with normal rat after the modeling, and the left back foot of AA rat can produce primary sacroiliitis rapidly, tangible swelling occurs, and with festering; Begin to occur Secondary cases sacroiliitis behind about 10 d of right back foot, the score value of scoring increases gradually; Ear's blood vessel hyperplasia is obvious simultaneously, and is obviously red and swollen; Swelling appears in caudal articular process.Vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors 1 immanoprotection action in adjuvanticity rat arthritis animal model, concrete outcome is as follows:
The influence of 1 pair of rat primary of vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors sacroiliitis foot pawl swelling degree, the left back ankle diameter of basic, normal, high dosage group of rat positive controls, vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors 1 and model group relatively have utmost point significant difference (P＜0.01); The vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitor left back ankle diameters of 1 basic, normal, high dosage group and model group relatively all have significant difference (P＜0.05), and experimental result has statistical significance.The influence of 1 pair of rat Secondary cases of vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors sacroiliitis foot pawl swelling degree, rat positive controls, the vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitor right back ankle diameters of 1 basic, normal, high dosage group and model group relatively have significant difference (P＜0.05).Vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors 1 I is to the influence of adjuvant type rats with arthritis clinical score, the scoring of the basic, normal, high dosage group of polypeptide I four limbs significantly is lower than model control group (P＜0.05), with the model control group comparing difference statistical significance is arranged all.The influence of 1 pair of adjuvant type of vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors rats with arthritis body weight, polypeptide 4 high, medium and low dosage group body weight are significantly higher than model control group (P＜0.05), with the model control group comparing difference statistical significance are arranged all.
Conclusion: 1 pair of AA rat arthritis of vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors has therapeutic action.
SEQUENCE LISTING
＜110〉Suzhou Pu Luoda bio tech ltd
＜120〉vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors 1 and application thereof
<130>
<160> 1
<170> Patent In version 3.3
<210> 1
<211> 7
<212> PRT
＜213〉artificial sequence
<400> 1
Val Cys Cys Ser Thr Arg Glu
1 5
Claims (2)
1. vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors 1 is characterized in that its sequence is Val-Cys-Cys-Ser-Thr-Arg-Glu.
2. vascular endothelial growth factor receptor 2 Tyrosylprotein kinase peptide inhibitors 1 are preparing the application for the treatment of in the medicine for treating rheumatoid arthritis.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772488A (en) * | 2014-01-21 | 2014-05-07 | 南通诚信氨基酸有限公司 | Polypeptide inhibitor modified with polyethylene glycol for inhibiting vascular endothelial growth factor receptors 2 tyrosine kinase and application thereof. |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103772488A (en) * | 2014-01-21 | 2014-05-07 | 南通诚信氨基酸有限公司 | Polypeptide inhibitor modified with polyethylene glycol for inhibiting vascular endothelial growth factor receptors 2 tyrosine kinase and application thereof. |
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Application publication date: 20130821 |