CN101618207B - 多肽在制备ace抑制剂及降血压药物中的应用 - Google Patents
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Abstract
本发明涉及抑制血管紧张素转换酶(angiotensin-converting enzyme,ACE)活性及降血压的一种多肽化合物VYNEGLPAP,其氨基酸序列分别为Val-Tyr-Asn-Glu-Gly-Leu-Pro-Ala-Pro。多肽VYNEGLPAP具有ACE抑制活性及降血压活性,作为高血压、心脏病和心血管病的保健品和药物先导化合物具有良好的应用前景。
Description
技术领域
本发明涉及多肽VYNEGLPAP在制备抑制血管紧张素转换酶(ACE)及降血压中的应用。
背景技术
高血压是一种常见的心血管疾病,发病率高、是引发心、脑、肾和血管等各种并发症和导致中风、促进动脉粥样硬化、冠心病的一个重要危险因子。我国高血压患者已超过1.6亿人口,治疗和预防高血压是当前社会十分重要的课题。肽是一类重要的降血压药物,肽降血压的作用靶点是抑制血管紧张素转化酶(angiotensin-converting enzyme,ACE)的活性(文献1:Vanessa Vermeirssen,John Van Camp,Willy Verstraete,British Journalof Nutrition 2004,92:357-366)。血管紧张素转化酶可将不具活性的十肽血管紧张素I转化为具有强烈收缩血管作用的八肽血管紧张素II,从而使血压升高,因此抑制ACE活性可有效控制高血压。多肽是一类重要的ACE抑制剂,天然蛋白质的酶解肽是ACE抑制剂肽的主要来源(文献2:Lieselot Vercruysse,John Van Camp,Guy Smagghe,J.Agric.Food Chem2005,53:8106-8115)。血管紧张素转化酶对于机体血压和心血管功能起着重要的调节作用,因此抑制ACE活性的药物在心血管、心力衰竭等疾病的治疗中发挥重要作用。多肽类的ACE抑制剂在降血压的同时不会引起常见降压药物的干咳等副作用。
发明内容
本发明的目的是提供多肽VYNEGLPAP在抑制ACE活性和降血压中的应用;多肽VYNEGLPAP具有ACE抑制活性及降血压活性,作为高血压、心脏病和心血管病的保健品和药物先导化合物具有良好的应用前景。
为实现上述目的,本发明以所述多肽VYNEGLPAP为抑制ACE活性和降血压的有效成份。
其具有序列表SEQ ID NO:1中氨基酸序列;多肽VYNEGLPAP为ACE抑制剂及降血压药物的活性成份,其中可添加药物学上可接受的载体或辅料。
具有抑制ACE活性和降血压活性的多肽化合物VYNEGLPAP的氨基酸序列为Val-Tyr-Asn-Glu-Gly-Leu-Pro-Ala-Pro。单链线性结构,分子量为959.7Da,白色粉末状,易溶于水,对ACE活性具有很强的抑制作用,IC50为3.1μM。。
多肽VYNEGLPAP具备ACE抑制剂所要求的特征:
1.ACE倾向于C末端三肽的每个位置含有疏水性氨基酸的底物或抑制剂,C末端为Try,Phe,Tyr和Pro而N端为支链氨基酸的肽段具有较强的ACE抑制活性。多肽VYNEGLPAP的C末端三肽均为疏水性氨基酸分别为Pro、Ala和Pro,C末端为Pro,N端的Val具有支链,因此完全满足要求。
2.肽的疏水性是影响其抑制活性的重要原因,抑制活性高的肽都含有较多的疏水氨基酸。多肽VYNEGLPAP的疏水氨基酸有Val,Tyr,Leu,Pro,Ala,和Pro含有较多的疏水氨基酸。
经ACE抑制活性检测,多肽VYNEGLPAP的IC50为0.00298mg/ml,即3.1μM。
本发明与现有技术相比,具有如下有益效果:
本发明首次从清原马鹿血中获得并确定了活性化合物的结构,化合物具有较好的抑制ACE的活性,因此作为治疗高血压等心血管疾病药物的先导化合物具有良好的潜力和应用前景。
具体实施方式
实施例1多肽VYNEGLPAP的制备
采用凝胶色谱和LC-MS/MS相结合的方法,以中国抚顺清原马鹿鹿血(Cervus elaphus)为原料,经离心,丙酮沉淀,酶解蛋白及柱分离获得乳白色粉末,溶于水。
其具体的提取分离方法如下:采用柱分离技术,用溶剂淋洗,凝胶层析柱与LC-MS/MS相结合,可按如下步骤分离提取操作:以清原马鹿鹿血(Cervus elaphus)为原料,取10-100毫升血浆蛋白,用60-200毫升的丙酮沉淀蛋白,弃上清,将沉淀离心,弃上清;将沉淀于40-100℃水浴,挥发丙酮并使蛋白变性;加入等体积5-1000毫摩尔,PH8.0,NH4HCO3缓冲液,按1∶10-500(质量比)加入蛋白酶,于30-100℃水浴,搅拌进行酶解1-12小时;50-100℃灭酶10-100分钟;上述酶解产物经SephadexG-25凝胶柱层析分离,将得到的不同组分冷冻干燥,为乳白色粉末状产品。
肽序列搜库:将经SephadexG-25凝胶柱层析后得到的组分分别用LTQ(线性离子阱四级杆)进行质谱分析,离子源为ESI,得到的数据在red.deer.fasta库中进行搜库检索,获得序列为Val-Tyr-Asn-Glu-Gly-Leu-Pro-Ala-Pro的多肽。
实施例2多肽VYNEGLPAP的ACE抑制活性检测
ACE在37℃、PH8.3的条件下催化分解血管紧张素I的模拟底物Hippuryl-L-Histidyl-L-Leucine(HHL)产生马尿酸,该物质在228nm处有特征紫外吸收峰。当加入ACE抑制物时,ACE对HHL的催化作用受到抑制,马尿酸的生成量会减少。通过测定加入抑制剂前后的马尿酸紫外吸收值可以计算出抑制活性的大小。
反应体系
缓冲液为0.05M,PH8.3硼酸盐缓冲液;底物为Hippuryl-L-Histidyl-L-Leucine(HHL),MW 429.47,用上述缓冲液配成5mM;ACE(angiotensin-converting enzyme)用上述缓冲液配成0.1U/ml。ODA(对照组,为不存在抑制剂但存在酶时的吸光值):50μl缓冲液+50ulHHL+50μl缓冲液于37℃水浴5min,然后加入50μ1ACE,37℃水浴30min,加入200μl,1M的HCl终止反应,再加入1ml乙酸乙酯萃取产物马尿酸,振荡15S,3500r/min离心5min,取0.8ml上清,90℃水浴干燥15min,重溶于0.8ml蒸馏水中,228nm处检测吸光值为ODA。ODB(样品组,为存在抑制剂和酶时的吸光值):50μl样品+50μ1HHL+50μl缓冲液于37℃水浴5min,然后加入50μ1ACE,37℃水浴30min,加入200μl,1M的HCl终止反应,再加入1ml乙酸乙酯萃取产物马尿酸,振荡15S,3500r/min离心5min,取0.8ml上清,90℃水浴干燥15min,重溶于0.8ml蒸馏水中,228nm处检测吸光值为ODB。
ODC(空白组,为不存在抑制剂和酶时的吸光值):50μl缓冲液+50μ1HHL+50μl缓冲液于37℃水浴5min,然后加入50μl缓冲液,37℃水浴30min,加入200μl,1M的HCl终止反应,再加入1ml乙酸乙酯萃取产物马尿酸,振荡15S,3500r/min离心5min,取0.8ml上清,90℃水浴干燥15min,重溶于0.8ml蒸馏水中,228nm处检测吸光值为ODC。
ACE抑制率(%)=(ODA-ODB)/(ODA-ODC)×100%
分别用0.5mg/ml,0.1mg/ml,0.01mg/ml,0.001mg/ml,0.0001mg/ml的浓度,按上述方法进行ACE抑制活性检测。结果如下表:
经IC50计算器计算该序列的IC50为0.00298mg/ml,即3.1μM。
ACE抑制剂
SEQUENCE LISTING
<110>中国科学院大连化学物理研究所
<120>多肽在制备ACE抑制剂及降血压药物中的应用
<130>
<160>1
<170>PatentIn version 3.1
<210>1
<211>9
<212>PRT
<213>Cervus elaphus
<220>
<221>CONFLICT
<222>(1)..(9)
<223>
<400>1
Val Tyr Asn Glu Gly Leu Pro Ala Pro
1 5
Claims (2)
1.多肽在制备ACE抑制剂及降血压药物中的应用,其特征在于:所述多肽为VYNEGLPAP。
2.按照权利要求1所述的应用,其特征在于:所述ACE抑制剂及降血压药物是以多肽VYNEGLPAP为活性成份,其中添加药物学上可接受的载体或辅料。
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CN104356209A (zh) * | 2014-08-28 | 2015-02-18 | 中国人民解放军第四军医大学 | 一种降低血压以及保护心脏的多肽 |
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CN1784146A (zh) * | 2003-05-05 | 2006-06-07 | 荷兰联合利华有限公司 | 具有血管紧张素转化酶抑制作用的肽 |
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