CN112125952A - 一种猪源ace抑制活性多肽与药物组合物或食品及应用 - Google Patents
一种猪源ace抑制活性多肽与药物组合物或食品及应用 Download PDFInfo
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- CN112125952A CN112125952A CN201910489870.2A CN201910489870A CN112125952A CN 112125952 A CN112125952 A CN 112125952A CN 201910489870 A CN201910489870 A CN 201910489870A CN 112125952 A CN112125952 A CN 112125952A
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- polypeptide
- ace
- leu
- inhibitory activity
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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Abstract
本发明涉及一种猪源ACE抑制活性多肽与药物组合物或食品及应用，具体为一种猪源的具有血管紧张素转换酶(angiotensin converting enzyme,ACE)抑制活性的多肽及其包含此活性多肽或其可接受的盐的组合物或食品。其氨基酸序列为Ala‑Val‑Ala‑Thr‑Leu‑Leu‑Lys‑Pro。多肽AVATLLKP具有ACE抑制活性以及降血压活性，作为高血压、心脏病和心血管病等疾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
本发明属于生物医药领域，具体涉及一种猪源ACE抑制活性多肽与药物组合物或食品及应用，活性多肽AVATLLKP在制备ACE抑制剂、降血压药物或食品中的应用。
背景技术
高血压是一种常见的心血管疾病，发病率高，其对心脏、脑、肾脏等靶器官具有严重损害，治疗和预防高血压是当前社会十分重要的课题。肾素-血管紧张素系统活性异常是高血压发病的主要原因，血管紧张素转换酶(angiotensin converting enzyme,ACE)对机体血压和心血管功能起到重要的调节作用。ACE能催化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。ACE抑制剂是目前治疗高血压与心力衰竭的主要有效药物。研究表明，普通的降压药具有作用时间短、停药后血压易反弹等特点，同时药物吸收排泄速度快会引起咳嗽、肾脏损伤及血管神经性水肿等副作用，而多肽类的ACE抑制剂只对高血压患者有效、对血压正常者无作用。天然蛋白质酶解产生的多肽是ACE抑制剂肽的主要来源，源于天然蛋白的ACE抑制肽作为降压药物或保健食品有着良好的应用前景。本发明即从猪源肽中筛选获得一个具有ACE抑制活性的肽。
发明内容
本发明的目的是提供从猪源肽中筛选获得一个具有ACE抑制活性的多肽AVATLLKP，该活性多肽或其药学上可接受的盐在抑制ACE活性和降血压药物中的应用；多肽AVATLLKP具有ACE抑制活性和降血压活性，作为高血压、心脏病和心血管病等疾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，本发明以从猪源获取的所述活性多肽AVATLLKP或其药学上可接受的盐为抑制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；活性多肽AVATLLKP或其药学上可接受的盐为ACE抑制剂、降血压药物和保健品的活性成分，其中可添加药物学上可接受的载体或辅料。
SEQ ID NO.1信息：
(a)序列特征
长度：303氨基酸
类型：氨基酸
链型：单链
(b)分子类型：蛋白质
序列描述：SEQ ID NO.1
MRIAVIAFCLWGFASALPVKQTNSGSSEEKLLSNKYTDAVATLLKPDPSQKQTFLAPQNTISSEETDDFKQETLPSKSNESPEQTDDVDDDDDEDHVDSRDTDSEEADHADDADRSDESHHSDESDELVTDFPTDTPATDVTPAVPTGDPNDGRGDSVVYGLRSKSKKFRRSEAQQLDATEEDLTSHVESEETDGTPKAILVAQRLHVASDLDSQEKDSQETSQPDDRSVETRSQEQSKEYTIKTYDGSNEHSNVIESQENPKVSQEFHSHEDKLVPDSKSEEDKHLKLRVSHELESASSEIN
活性多肽为AVATLLKP的衍生多肽或其药学上可接受的盐，其中所衍生的多肽为在SEQ ID NO：1所示氨基酸序列经过取代、缺失和/或添加一个或几个氨基酸且与上述活性多肽或其药学上可接受的盐具有相同功能的衍生多肽。
具有抑制ACE活性和降血压活性的多肽AVATLLKP，氨基酸序列为Ala-Val-Ala-Thr-Leu-Leu-Lys-Pro，为单链线性结构，白色粉末状，易溶于水，分子量为812.02Da；对ACE活性具有较强抑制作用，半抑制浓度(IC50)为26.36μM。
ACE抑制肽结构与活性关系的研究表明，抑制剂的C端三肽强烈影响其与ACE的结合，ACE倾向于C端三肽每个位置含有疏水性氨基酸(芳香族氨基酸和支链氨基酸)的抑制剂。
1.C末端为芳香族氨基酸(Trp、Tyr、Phe)或Pro而N端为疏水氨基酸的肽段具有较强的ACE抑制活性。多肽AVATLLKP的C末端氨基酸为Pro，N末端为疏水氨基酸Ala，满足要求。
2.C末端第二位氨基酸对活性的影响较小，但更倾向于电荷指数(electroniccharge index,ECI)、疏水性和侧链体积较小的氨基酸，如Ala、Gly、Lys和Val等。多肽AVATLLKP的C末端第二位氨基酸为Lys，满足要求。
3.C末端第三位氨基酸的电荷指数对活性的影响很大，与ACE抑制活性呈负相关。当该位置氨基酸电荷指数小而疏水性强时，ACE抑制肽活性强。满足这些条件的氨基酸主要为Phe、Trp、Tyr、Met、Ile、Leu和Val等。多肽AVATLLKP的C末端第三位氨基酸为Leu，满足条件。
4.肽的疏水性氨基酸含量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AVATLLKP的疏水氨基酸分别有Ala、Val、Ala、Leu、Leu和Pro，疏水氨基酸占序列总氨基酸数目的75％。
该活性多肽或其药学上可接受的盐在ACE抑制剂及降血压药物中的应用，在制备ACE抑制剂及降血压药物和/或食品中的应用。或在药物组合物或食品中添加该活性多肽或其药学上可接受的盐。
本发明与现有技术相比，具有如下有益效果：
本发明首次从猪源肽中获得并确定了一种具有良好ACE抑制活性的化合物的结构，其对ACE的IC50为26.36μM。该发现进一步拓展了ACE抑制肽的来源，为来源于天然蛋白的ACE抑制肽的研究提供参考。
具体实施方法
实施例1多肽AVATLLKP的筛选与鉴定
采用LC-MS/MS与Shotgun蛋白质组学技术相结合的方法。以猪四肢骨为原料，经水煎煮、乙醇沉淀、酸沉淀、碱沉淀等处理后得到猪骨提取物，提取物经过离心、超滤、除盐处理后进行LC-MS/MS分析，结合构效关系特征，筛选对ACE具有抑制作用的肽段。
其具体方法如下：
样品制备：(1)提取：新鲜猪四肢骨洗净、粉碎、称重，按料液比1:2(w/v)加入水，1.2MPa热压提取1.5h，过滤，重复提取一次，合并滤液。(2)去脂：滤液4℃冷却静置36h，去除上层脂肪。(3)乙醇沉淀：真空浓缩，浓缩液冷却后加入乙醇至终浓度为70％(v/v)，静置沉淀36h，过滤除去杂蛋白。(4)酸沉淀：滤液再次浓缩后，加盐酸调节至pH为4.0，100℃加热45min，4℃静置24h，过滤除去酸性杂蛋白。(5)碱沉淀：氢氧化钠调节滤液至pH为8.5，100℃加热45min，4℃静置24h，过滤除去碱性杂蛋白。(6)调节pH：将滤液加入盐酸调节至pH为7.0，4℃静置24h，过滤。(7)吸附：滤液中按0.5％加入活性炭，100℃加热30min，过滤，滤液冻干。将猪骨提取物冻干粉加入适量水溶解，离心、超滤后使用C18-SPE柱(固相萃取柱，美国Waters公司)除盐。
除盐方法：适量甲醇活化SPE柱，用0.1％(v/v)的三氟乙酸(TFA)溶液平衡柱子，样品调节至酸性(pH 2-3)后上样，0.1％(v/v)TFA溶液洗盐，最后使用80％(v/v)乙腈和0.1％(v/v)TFA溶液洗脱。
质谱分析：除盐后的样品冻干，加适量0.1％甲酸水复溶，使用线性离子阱静电场轨道阱组合质谱仪(LTQ Orbitrap Velos)对样品进行质谱分析，样品平行分析两次，取两次分析鉴定到的共同肽段进行统计。
肽序列搜库：将样品用LTQ Orbitrap Velos进行质谱分析，谱图在猪科蛋白库suidae.fasta(https://www.uniprot.org/)中进行检索。两次分析共鉴定到来源于16个不同蛋白的198条共同肽段。根据发明内容中关于构效关系的阐述，对鉴定到的共同肽段进行筛选，获得来源于骨桥蛋白(Osteopontin)的序列为AVATLLKP的多肽。鉴定到来源于骨桥蛋白的共同肽段的信息如表1所示。
表1注射用骨肽中鉴定到的共同肽段
实施例2多肽AVATLLKP的ACE抑制活性检测
原理
N-[3-(2-呋喃基)丙烯酰]-L-苯丙氨酰-甘氨酰-甘氨酸(FAPGG，λmax＝340nm，ε＝2270M-1cm-1，分子量399.40)可以被ACE酶解成N-[3-(2-呋喃基)丙烯酰]-L-苯丙氨酰(FAP，λmax＝340nm，ε＝1512M-1cm-1)和甘氨酰-甘氨酸(GG，在340nm处无吸收)，因此可以作为ACE的模拟底物。1mM FAPGG完全转化成FAP和GG的吸光值为0.758，可根据340nm吸光度的变化值计算抑制率。
反应体系
(1)缓冲溶液：0.1M PBS缓冲液(pH 8.2，含300mM NaCl)
(2)底物溶液：使用上述缓冲液配制浓度为1.6mM的FAPGG溶液。
(3)酶溶液：使用上述缓冲溶液将ACE配制成0.2U/mL的溶液。
(4)样品溶液：按照实验需要将多肽AVATLLKP用上述缓冲液配制成不同浓度的溶液。
实验在96孔板中进行。按照表2依次加入样品溶液、ACE溶液和底物溶液，混合均匀，立即用酶标仪于340nm波长下测定吸光度，记为A0。37℃温育30min后再次于340nm波长下测定吸光度，记为A1。测定各个样品的孔的吸光度，令ΔA＝A0-A1。每个样品平行测定3次。
表2 ACE抑制活性加样方法
“-”代表加入该列等体积的PBS缓冲液
抑制率计算公式：
I＝[1-(ΔASample-ΔAblank)/(ΔAControl-ΔAblank)]╳100％
其中I表示抑制率，ΔAcontrol表示对照组0min与30min时吸光度值的差值；ΔAsample表示样品组0min与30min时吸光度值的差值。
分别用不同的浓度，按上述方法对多肽AVATLLKP进行ACE抑制活性检测。结果如表3所示：
表3多肽AVATLLKP的ACE抑制活性
经IC50计算器计算该序列的IC50为26.36±0.56μM，R2＝0.9983。
根据BIOPEP数据库中的收录结果，目前已知的ACE抑制活性肽主要为氨基酸数量较少的短肽，IC 50值大多为几微摩尔至几十微摩尔。该发明中活性多肽AVATLLKP的IC 50值为26.36μM，在目前已知的ACE抑制活性肽中属于ACE抑制能力较强的多肽，且来源广泛、天然、安全，因此作为一种高血压、心脏病和心血管病等疾病的保健品和药物先导化合物具有良好的应用前景。
序列表
<110> 中国科学院大连化学物理研究所
<120> 一种猪源ACE抑制活性多肽与药物组合物或食品及应用
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<213> 人工序列(Artificial Sequence)
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Leu Pro Val Lys Gln Thr Asn Ser Gly Ser Ser Glu Glu Lys Leu Leu
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Ser Asn Lys Tyr Thr Asp Ala Val Ala Thr Leu Leu Lys Pro Asp Pro
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Ser Gln Lys Gln Thr Phe Leu Ala Pro Gln Asn Thr Ile Ser Ser Glu
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Glu Thr Asp Asp Phe Lys Gln Glu Thr Leu Pro Ser Lys Ser Asn Glu
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Ser Pro Glu Gln Thr Asp Asp Val Asp Asp Asp Asp Asp Glu Asp His
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Val Asp Ser Arg Asp Thr Asp Ser Glu Glu Ala Asp His Ala Asp Asp
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Ala Asp Arg Ser Asp Glu Ser His His Ser Asp Glu Ser Asp Glu Leu
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Val Thr Asp Phe Pro Thr Asp Thr Pro Ala Thr Asp Val Thr Pro Ala
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Val Pro Thr Gly Asp Pro Asn Asp Gly Arg Gly Asp Ser Val Val Tyr
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Gly Leu Arg Ser Lys Ser Lys Lys Phe Arg Arg Ser Glu Ala Gln Gln
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Leu Asp Ala Thr Glu Glu Asp Leu Thr Ser His Val Glu Ser Glu Glu
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Thr Asp Gly Thr Pro Lys Ala Ile Leu Val Ala Gln Arg Leu His Val
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Ala Ser Asp Leu Asp Ser Gln Glu Lys Asp Ser Gln Glu Thr Ser Gln
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Pro Asp Asp Arg Ser Val Glu Thr Arg Ser Gln Glu Gln Ser Lys Glu
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Tyr Thr Ile Lys Thr Tyr Asp Gly Ser Asn Glu His Ser Asn Val Ile
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Glu Ser Gln Glu Asn Pro Lys Val Ser Gln Glu Phe His Ser His Glu
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Asp Lys Leu Val Pro Asp Ser Lys Ser Glu Glu Asp Lys His Leu Lys
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Leu Arg Val Ser His Glu Leu Glu Ser Ala Ser Ser Glu Ile Asn
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Claims (5)
1.一种猪源ACE抑制活性多肽，其特征在于：活性多肽为AVATLLKP或其药学上可接受的盐，所述活性多肽具有序列表SEQ ID NO.1中氨基酸序列；该活性多肽的氨基酸序列具体为Ala-Val-Ala-Thr-Leu-Leu-Lys-Pro。
2.按照权利要求1所述的活性多肽，其特征在于：活性多肽为AVATLLKP的衍生多肽或其药学上可接受的盐，其中所衍生的多肽为在SEQ ID NO：1所示氨基酸序列经过取代、缺失和/或添加一个或几个氨基酸且与权利要求1所述活性多肽或其药学上可接受的盐具有相同功能的衍生多肽。
3.权利要求1～2任一项所述的活性多肽或其药学上可接受的盐在血管紧张素转换酶(angiotensin converting enzyme,ACE)抑制剂及降血压药物中的应用。
4.一种药物组合物或食品，其中包括权利要求1～2任一项所述的活性多肽或其药学上可接受的盐。
5.按照权利要求4所述的药物组合物或食品，其特征在于：所述药物组合物或食品在制备ACE抑制剂及降血压药物和/或食品中的应用。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001233895A (ja) * | 2000-02-23 | 2001-08-28 | Mie Prefecture | ブタ内臓由来のアンジオテンシン変換酵素阻害物質およびその製造方法 |
| US20040014670A1 (en) * | 2001-01-16 | 2004-01-22 | Ajinomoto Co. Inc | Inhibitors of angiotensin converting enzyme |
| CN101955512A (zh) * | 2009-12-22 | 2011-01-26 | 大连水产学院 | 血管紧张素ⅰ转换酶活性抑制寡肽、制备方法及其应用 |
-
2019
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001233895A (ja) * | 2000-02-23 | 2001-08-28 | Mie Prefecture | ブタ内臓由来のアンジオテンシン変換酵素阻害物質およびその製造方法 |
| US20040014670A1 (en) * | 2001-01-16 | 2004-01-22 | Ajinomoto Co. Inc | Inhibitors of angiotensin converting enzyme |
| CN101955512A (zh) * | 2009-12-22 | 2011-01-26 | 大连水产学院 | 血管紧张素ⅰ转换酶活性抑制寡肽、制备方法及其应用 |
Non-Patent Citations (2)
| Title |
|---|
| YU-TSE LIU ET AL.: ""Production, Analysis and in Vivo Antihypertensive Evaluation of Novel Angiotensin-I-converting Enzyme Inhibitory Peptides from Porcine Brain"", 《FOOD SCIENCE AND TECHNOLOGY RESEARCH》 * |
| 王晓丹 等: ""ACE抑制肽构效关系研究进展"", 《食品科学》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114539358A (zh) * | 2020-11-19 | 2022-05-27 | 中国科学院大连化学物理研究所 | 一种多肽及制备方法与应用 |
| CN114539358B (zh) * | 2020-11-19 | 2023-09-15 | 中国科学院大连化学物理研究所 | 一种多肽及制备方法与应用 |
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