CN104558110B - 具有ace抑制活性的多肽及其在降血压药物中的应用 - Google Patents
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Abstract
本发明涉及一种具有ACE抑制活性的多肽化合物AELDIVLALF，其氨基酸序列分别为Ala‑Glu‑Leu‑Asp‑IIe‑Val‑Leu‑Ala‑Leu‑Phe。多肽AELDIVLALF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AELDIVLALF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 Nutrition2004，92：357-366）。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.FoodChem2005,53:8106-8115）。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AELDIVLALF在抑制ACE活性和降血压中的应用；多肽AELDIVLALF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AELDIVLALF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AELDIVLALF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AELDIVLALF的氨基酸序列为Ala-Glu-Leu-Asp-IIe-Val-Leu-Ala-Leu-Phe。单链线性结构，分子量为1103.3Da，白色粉末状，易溶于水，对ACE活性具有很强的抑制作用，IC50为10.6μM。
多肽AELDIVLALF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AELDIVLALF的C末端三肽均为疏水性氨基酸分别为Ala、Leu和Phe，C末端为Phe，因此满足ACE抑制剂的绝大部分要求。
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AELDIVLALF的疏水氨基酸有Ala，Val，Leu，Phe，IIe，含有较多的疏水氨基酸。
经ACE抑制活性检测，多肽AELDIVLALF的IC50为10.6μM。
本发明与现有技术相比，具有如下有益效果：
本发明首次从油菜花粉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、心脏病等心血管疾病药物和保健品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AELDIVLALF的制备
20g油菜蜂花粉加入液氮研磨破壁后，加入pH=7.4、50mM Tris-HCl缓冲液150ml,超声提取三次（一次：400W，超声4s，停4s，80个循环）；提取结束后于4℃、25000g离心1h，取上清液，加入上清液4倍体积的混合溶剂（丙酮：乙醇：乙酸=50:50:0.1（体积比））沉淀过夜；沉淀结束后将所有样品于4℃、25000g离心30分钟，弃去上清，取沉淀用丙酮洗涤脱色，然后于4℃、25000g离心15分钟，弃去上清，沉淀继续用丙酮反复洗涤直至上清无色，最后用体积浓度75%乙醇洗涤沉淀并于4℃、25000g离心10分钟，弃上清，取沉淀物冷冻干燥，得冻干蛋白。冻干蛋白用含有8M尿素的pH=7.4、100mM NH4HCO3缓冲液复溶，以酶：蛋白=1:25（w/w）比例加入胰蛋白酶，37℃酶解20小时。上述酶解产物经制备色谱分离，色谱柱为C18（20X250mm，10μm）,所用的流动相A为质量浓度0.1%甲酸/水溶液，流动相B为质量浓度0.1%的甲酸/乙腈溶液，流速为2mL/min，洗脱过程如下：5%B—35%B(V/V)—80%B(V/V)。将在280nm下所检测到的色谱峰分别收集得到不同组分冷冻干燥，为乳白色粉末状样品。
所得样品经反相液相色谱-串联质谱系统（RPLC-MS/MS）分析：将冷冻干燥后的酶解样品用体积浓度0.1%甲酸溶液配制为0.4μg/μL，进样20μL进行LTQ线性离子阱质谱（配置纳升级电喷雾源）分析。利用Xcalibur软件(Thermo)进行系统控制和数据收集。实验得到的质谱数据结果分别在honeybee,Brassica campestris L.蛋白质数据库（http://www.uniprot.org/）中进行检索，技术重复3次，数据库检索软件为SEQUEST。获得序列为Ala-Glu-Leu-Asp-IIe-Val-Leu-Ala-Leu-Phe。
实施例2多肽AELDIVLALF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)，MW429.47，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50μl ACE，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（多肽样品组，为存在抑制剂和酶时的吸光值）:50μl样品+50μlHHL+50μl缓冲液于37℃水浴5min，然后加入50μlACE，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+50μlHHL+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0.0495mg/ml,0.02475mg/ml,0.01485mg/ml,0.00495mg/ml的多肽浓度，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11.70μg/mL，即10.6μM。
Claims (3)
1.具有ACE抑制活性的多肽，其特征在于：所述多肽为AELDIVLALF，具有序列表SEQ IDNO：1 中氨基酸序列；该多肽的氨基酸序列具体为，Ala-Glu-Leu-Asp-IIe-Val-Leu-Ala-Leu-Phe。
2.一种权利要求1所述多肽在制备ACE抑制剂或降血压药物中的应用。
3.按照权利要求2所述的应用，其特征在于：所述ACE抑制剂或降血压药物是以多肽AELDIVLALF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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| CN1812776A (zh) * | 2003-05-21 | 2006-08-02 | 得克萨斯州大学系统董事会 | 抑制蛋白激酶c－mu(pkd)用作心脏肥大和心力衰竭的疗法 |
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