CN101361961A - Use of polypeptides micro-molecule in preparing medicine for preventing and treating ischemic cerebrovascular disease - Google Patents
Use of polypeptides micro-molecule in preparing medicine for preventing and treating ischemic cerebrovascular disease Download PDFInfo
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- CN101361961A CN101361961A CNA2008102006100A CN200810200610A CN101361961A CN 101361961 A CN101361961 A CN 101361961A CN A2008102006100 A CNA2008102006100 A CN A2008102006100A CN 200810200610 A CN200810200610 A CN 200810200610A CN 101361961 A CN101361961 A CN 101361961A
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Abstract
The invention relates to the technical field of biological medicines, which is an application of a small polypeptide molecule in preparing a drug for preventing ischemic cerebrovascular disease. The research of the invention finds out that polypeptide bioactive molecules and polypeptide spliceosomes extracted from the secretion of amoeba histolytica have the pharmacological action of preventing ischemic cerebrovascular disease. The pentapeptide and tripeptide are proved to be capable of remarkably reducing the brain damage to the mouse caused by ischemia-reperfusion and remarkably improving the neuro behavioral of the mouse after ischemia by the results of pharmacological experiment on mouse models with focal cerebral ischemia. Compared with the kindred protein drugs, the small polypeptide molecule has strong brain protection effects; in addition, molecular weight is small, thereby being easy to permeate blood-brain barrier and having remarkable advantage of brain permeability. Therefore, the small polypeptide molecule provided has good application prospect in preparing the drug for preventing the ischemic cerebrovascular disease.
Description
Technical field
The present invention relates to the biological medicine technology field, be specifically related to the application of polypeptide small molecule in preparation control ischemic cerebrovascular medicine.
Background technology
Ischemic cerebrovascular (cerebral infarction) is one of sickness rate, mortality rate, disease that disability rate is the highest in the world, is greatly threatening human, old people's Health and Living quality particularly, has become the great burden of global Community health resource.In nervous system disease, accounted for the first place with cerebral infarction mortality rate and disability rate clinically.Domestic and international application in the active drug for the treatment of ischemic cerebrovascular seldom at present.Therefore, the medical treatment of carrying out ischemic cerebrovascular in a deep going way is studied significant.
A kind of polypeptide of anti-inflammatory response claims mononuclear cell migration inhibitory factor (MLIF) again, is the pentapeptide of finding from the Entamoeba histolytica of aseptic culture (Met-Gln-Cys-Asn-Ser).Experimental results show that in In vitro culture and the body that this Toplink suppresses moving of person monocytic cell, polymorphonuclear leukocyte.Entamoeba histolytica influences cytokine secretion by producing this anti-inflammatory polypeptide, and host immune is escaped in the generation of restriction inflammation.Bibliographical information, this pentapeptide molecule not only can directly act on inflammatory cell, also can influence the process of inflammatory reaction by the secretion of disturbing inflammatory cytokine, inflammation chemotactic factors such as MIP-1 α, MIP-1 β there is significant inhibitory effect, can also suppresses inflammatory cytokine secretion and corresponding receptor expression such as IL-1 β, TNF-α simultaneously.
Up to now, this polypeptide of Shang Weijian is used for the report of cerebrovascular disease.
Summary of the invention
The present invention discovers that this pentapeptide bioactive molecule that extracts and polypeptide spliceosome have the pharmacological action of control ischemic cerebrovascular from the juice of amoeba histolytica.
The invention provides the application of the pentapeptide of aminoacid sequence shown in SEQ ID NO:1 in preparation control ischemic cerebrovascular medicine.
Simultaneously, the present invention has also found the tripeptides that last three aminoacid are formed in this pentapeptide to the research of this pentapeptide spliceosome, and aminoacid sequence has the activity of control ischemic cerebrovascular equally shown in SEQ ID NO:2.
The present invention is through the pharmacological testing of mice focal cerebral ischemia model, and the result shows that this pentapeptide molecule and tripeptides molecular energy significantly reduce the brain injury area that the mouse brain ischemia-reperfusion causes, and significantly improves the neurobehavioral behind the mice ischemia.Compare with similar protein drug, this polypeptide small molecule cerebral protection is strong; And, be easy to penetrating blood brain barrier because molecular weight is little, have the saturating sexual clorminance of significant nicergoline.
Polypeptide small molecule of the present invention pharmaceutics routinely is prepared into injection, tablet or capsule.
Polypeptide small molecule provided by the invention has good prospects for application in preparation control ischemic cerebrovascular medicine.
The specific embodiment
Embodiment 1: the preparation method of polypeptide small molecule
1, the aminoacid sequence of pentapeptide is shown in SEQ ID NO:1: Met-Gln-Cys-Asn-Ser
2, the aminoacid sequence of tripeptides is shown in SEQ ID NO:2: Cys-Asn-Ser
Above pentapeptide and three peptide molecules are given birth to worker's biotechnology company by Shanghai and are synthesized, and purity is more than 95%.
Embodiment 2: polypeptide small molecule is used for the treatment of the zoopery of ischemic cerebrovascular
The pharmacological evaluation that mice line bolt legal system is made the focal cerebral ischemia model is that the checking medicine has control ischemic cerebrovascular effect zoopery (Yin XM commonly used, Luo Y, Cao G, Bai L, Pei W, KuharskyDK, Chen J.Bid-mediated mitochondrial pathway is critical to ischemic neuronalapoptosis and focal cerebral ischemia.J Biol Chem.2002 Nov1; 277 (44): 42074-81.), therefore verify of the protective effect of this peptide molecule to the experimental animal models cerebral ischemia with it.
1, animal
The C57/6BL mice, male, body weight 20～24g, every group of 10/cage group support is divided into 8 groups.Purchase in Chinese Academy of Sciences's Shanghai Experimental Animal Center (animal quality certification number: No. 99-003, middle section Shanghai moving pipe word).Raise in cleaning level Animal House.
2, medicine
Experiment mice is divided into groups:
1 group of medicine: give pentapeptide 0.5mg/kg.
2 groups of medicines: give pentapeptide 1.0mg/kg.
3 groups of medicines: give tripeptides 0.5mg/kg.
4 groups of medicines: give tripeptides 1.0mg/kg.
Blank group: give to carry out sham-operation with the normal saline of drug study group equivalent.
Model group: give to carry out the cerebral ischemia re-pouring operation with the normal saline of drug study group equivalent.
3, experimental technique
With mice with 10% chloral hydrate intraperitoneal injection of anesthesia, neck median incision, separation, ligation right carotid proximal part, external carotid artery and bifurcated artery thereof.Separate the right side internal carotid artery, separate wing jaw tremulous pulse downwards along internal carotid artery, this branch of root ligation.Be equipped with line, far-end placement bulldog clamp at the internal carotid artery near-end, common carotid artery crotch otch inserts 4-0 nylon wire, and the bolt line enters internal carotid artery, goes into cranium to anterior cerebral artery, all blood flows sources of blocking-up middle cerebral artery.Remove bulldog clamp, tighten line fully, stay the long the end of a thread of 1cm outward, skin suture.Ischemia is the tail intravenously administrable after 1 hour.Continue ischemia perfusion again after 1 hour.Sham operated rats is except that plug wire not, and all the other steps are the same.
(1) medicine is to the influence of mouse brain ischemia-reperfusion injury model behavioristics scoring
After the survival Mus pours into 24 again, observe the mice behavior and change, carry out behavior scoring.5 fens system standards of grading with reference to Zea Longa: 0 minute, normal, impassivity damage symptom; 1 minute, can not full extension offside fore paw; 2 minutes, turn-take laterally; 3 minutes, topple over to offside; 4 minutes, can not spontaneously walk loss of consciousness.The result shows: the blank group, and model group, one group of medicine, two groups of medicines, three groups of medicines, behavioristics's scoring (branch) that medicine is four groups is followed successively by: 0; 3.0 ± 0.71; 2.0 ± 0.82; 1.5 ± 0.24; 2.5 ± 0.97; 1.8 ± 0.45.Wherein, remove blank group, two groups of behavioristics's scorings than other groups of medicine are minimum.Show therapeutic effect the best of two groups of medicines in the subordinate act scoring, promptly when the dosage that gives pentapeptide was 1.0mg/kg, the cerebral infarction that the mouse brain ischemical reperfusion injury is caused was plugged with remarkable protective effect.See Table 1.
(2) medicine is to the influence of mouse brain ischemia-reperfusion injury model cerebral infarct size
After the survival Mus poured into 24 again, broken end was got the Mus brain fast.Downcut the crown brain sheet of thick about 2mm on the anterior commissure plane, place 2%TTC solution at once, hatched 30 minutes for 37 ℃.Infarct presents white, and non-infarct presents redness.Measure with planimeter (C63 image analysis system) and respectively to distinguish area, and calculate the percentage ratio (%) that infarct accounts for whole crown.The result shows: the cerebral infarct size of model group (%) is 35.0 ± 5.8, the cerebral infarct size that medicine is one group (%) is 23.6 ± 4.7, the cerebral infarct size that medicine is two groups (%) is 15.3 ± 7.9, the cerebral infarct size that medicine is three groups (%) is 28.5 ± 4.4, and the cerebral infarct size that medicine is four groups (%) is 19.9 ± 8.1.Wherein, two groups of side cerebral tissue of medicine infarct size is significantly less than other, and has compared significant difference (P＜0.01) with each group.Promptly when the dosage that gives pentapeptide was 1.0mg/kg, the cerebral infarction that the mouse brain ischemical reperfusion injury is caused was plugged with remarkable protective effect.See Table 2.
Behavioristics's scoring behind the mouse brain ischemia-reperfusion (x ± s) is respectively organized in table 1 experiment
Compare with model group,
*P＜0.01,
*P＜0.05
Cerebral infarct size behind the mouse brain ischemia-reperfusion (x ± s) is respectively organized in table 2 experiment
Compare with model group,
*P＜0.01
SEQUENCE?LISTING
＜110〉Second Military Medical University, PLA
＜120〉application of polypeptide small molecule in preparation control ischemic cerebrovascular medicine
＜130〉description, claims
<160>2
<170>PatentIn?version?3.1
<210>1
<211>5
<212>PRT
＜213〉artificial sequence
<400>1
<210>2
<211>3
<212>PRT
＜213〉artificial sequence
<400>2
Claims (2)
1, the application of polypeptide small molecule in preparation control ischemic cerebrovascular medicine, the aminoacid sequence of this polypeptide small molecule is shown in SEQ ID NO:1 or SEQ ID NO:2.
2, the application of polypeptide small molecule according to claim 1 in preparation control ischemic cerebrovascular medicine, polypeptide small molecule wherein pharmaceutics routinely is prepared into injection, tablet or capsule.
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| CN101361961A true CN101361961A (en) | 2009-02-11 |
| CN101361961B CN101361961B (en) | 2011-12-21 |
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Cited By (10)
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| CN101822815A (en) * | 2010-04-29 | 2010-09-08 | 广东八加一医药有限公司 | Application of series of small-molecule peptides in preparing medicament for preventing and treating ischemic cerebrovascular disease |
| WO2011009382A1 (en) * | 2009-07-23 | 2011-01-27 | 中国人民解放军第二军医大学 | Use of polypeptide micromolecule mlif in preparing medicine for preventing and treating myocardial ischemia |
| CN103421087A (en) * | 2013-04-12 | 2013-12-04 | 上海捌加壹医药科技有限公司 | Liquid-phase synthesizing method for polypeptide |
| CN105968187A (en) * | 2016-06-07 | 2016-09-28 | 南京医科大学附属脑科医院 | Angiogenesis agonist polypeptide and application |
| CN106046146A (en) * | 2016-06-07 | 2016-10-26 | 南京医科大学附属脑科医院 | Angiogenic agonist polypeptide and application thereof |
| CN106188235A (en) * | 2016-08-10 | 2016-12-07 | 武汉弘跃医药科技有限公司 | A kind of synthetic peptide treating nervous system disease |
| CN106188229A (en) * | 2016-08-10 | 2016-12-07 | 武汉弘跃医药科技有限公司 | A kind of be pharmacologically active group with free glycine and L cysteine synthetic peptide |
| CN106188236A (en) * | 2016-02-05 | 2016-12-07 | 武汉弘跃医药科技有限公司 | A kind of containing glycine, L cysteine, the synthetic peptide of L phenylalanine and application thereof |
| CN106220709A (en) * | 2016-08-10 | 2016-12-14 | 武汉弘跃医药科技有限公司 | A kind of easily through the synthetic peptide of blood brain barrier |
| CN109517031A (en) * | 2018-12-21 | 2019-03-26 | 闫龙飞 | A kind of oligopeptide compounds and its preparation method and application |
Families Citing this family (1)
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| CN103203009B (en) * | 2013-04-15 | 2015-07-15 | 中国人民解放军第二军医大学 | New application of partial metabolite of pentapeptide in preparation of myocardial ischemia resistant product |
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- 2008-09-27 CN CN2008102006100A patent/CN101361961B/en active Active
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2011009382A1 (en) * | 2009-07-23 | 2011-01-27 | 中国人民解放军第二军医大学 | Use of polypeptide micromolecule mlif in preparing medicine for preventing and treating myocardial ischemia |
| CN101612384B (en) * | 2009-07-23 | 2012-06-20 | 中国人民解放军第二军医大学 | Application of polypeptide small molecule MLIF in preparing medicine for preventing and treating myocardial ischemia |
| US8343921B2 (en) | 2009-07-23 | 2013-01-01 | Shanghai Bajiayi Pharmaceutical Science And Technology Co. Ltd. | Method for treating myocardial ischemia |
| CN101822815A (en) * | 2010-04-29 | 2010-09-08 | 广东八加一医药有限公司 | Application of series of small-molecule peptides in preparing medicament for preventing and treating ischemic cerebrovascular disease |
| CN103421087A (en) * | 2013-04-12 | 2013-12-04 | 上海捌加壹医药科技有限公司 | Liquid-phase synthesizing method for polypeptide |
| CN106188236A (en) * | 2016-02-05 | 2016-12-07 | 武汉弘跃医药科技有限公司 | A kind of containing glycine, L cysteine, the synthetic peptide of L phenylalanine and application thereof |
| CN106046146A (en) * | 2016-06-07 | 2016-10-26 | 南京医科大学附属脑科医院 | Angiogenic agonist polypeptide and application thereof |
| CN105968187A (en) * | 2016-06-07 | 2016-09-28 | 南京医科大学附属脑科医院 | Angiogenesis agonist polypeptide and application |
| CN106188235A (en) * | 2016-08-10 | 2016-12-07 | 武汉弘跃医药科技有限公司 | A kind of synthetic peptide treating nervous system disease |
| CN106188229A (en) * | 2016-08-10 | 2016-12-07 | 武汉弘跃医药科技有限公司 | A kind of be pharmacologically active group with free glycine and L cysteine synthetic peptide |
| CN106220709A (en) * | 2016-08-10 | 2016-12-14 | 武汉弘跃医药科技有限公司 | A kind of easily through the synthetic peptide of blood brain barrier |
| CN106188235B (en) * | 2016-08-10 | 2019-09-17 | 武汉弘跃医药科技有限公司 | A kind of synthetic peptide for treating the nervous system disease |
| CN106220709B (en) * | 2016-08-10 | 2019-09-17 | 武汉弘跃医药科技有限公司 | A kind of easy synthetic peptide through blood-brain barrier |
| CN109517031A (en) * | 2018-12-21 | 2019-03-26 | 闫龙飞 | A kind of oligopeptide compounds and its preparation method and application |
| CN109517031B (en) * | 2018-12-21 | 2022-01-25 | 闫龙飞 | Oligopeptide compound and preparation method and application thereof |
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| CN101361961B (en) | 2011-12-21 |
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Effective date of registration: 20231008 Address after: No. 10 Mulan North Street, Guilin Economic and Technological Development Zone, Guangxi Zhuang Autonomous Region, 541000 Patentee after: Bajiayi Pharmaceutical Co.,Ltd. Address before: Room 2310, Building 4, Yunjing Mingdu, No. 89 Jingxi Road, Baiyun District, Guangzhou City, Guangdong Province, 510515 Patentee before: GUANGDONG 8PLUS1 MEDICINE Co.,Ltd. |