CN110467653A - 一种抑制血管紧张素转换酶活性的多肽及其应用 - Google Patents
一种抑制血管紧张素转换酶活性的多肽及其应用 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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Abstract
本发明提供了一种抑制血管紧张素转换酶活性的多肽及其应用,属于生物技术领域。本发明所述多肽的氨基酸序列如SEQ ID NO.1所示(Pro‑Gly‑Asp‑Arg‑Asp‑Asn‑Leu),针对ACE靶标均具有抑制活性,从而表现出同时具有降血压的特性;且多肽的活性与浓度存在量效关系,属于新的具ACE抑制活性功能肽,可将其用于制备ACE抑制剂或降压药物。
Description
技术领域
本发明属于生物技术领域,具体涉及一种抑制血管紧张素转换酶活性的多肽及其应用。
背景技术
血管紧张素转换酶(Angiotensin converting enzyme,ACE)是一种二羧肽酶,是导致高血压的一个关键酶,它通过水解作用把血管紧张肽I转化成血管紧张肽Ⅱ,与此同时,ACE还可钝化血管舒缓激肽,这两种作用均可导致血管收缩,从而引起高血压。因此ACE被认为是引起高血压的一个重要因素。
目前,常见的降压药物主要有以下几类:
①利尿剂:代表药物有氢氯噬嗓、氨苯蝶吮、螺内酉旨等。
②片受体阻滞剂:代表药物有普蔡洛尔、美托洛尔、阿替洛尔、纳多洛尔等。
③钙通道阻滞剂:代表药物有硝苯地平、氨氯地平、非洛地平、尼群地平、拉西地平等。
④血管紧张素转换酶抑制剂:代表药物有卡托普利、苯那普利、赖诺普利、依那普利、西拉普利等。
⑤α-受体阻滞剂:代表药物有呱哇嗓、特拉哩嗦等。
⑥血管紧张素Ⅱ受体拮抗剂:代表药物有洛沙坦、撷沙坦、厄贝沙坦、坎地沙坦、伊贝沙坦、替米沙坦等。
但是上述药物存在副作用强烈的缺点。
经研究发现血管紧张素转换酶抑制剂(ACEI),可通过抑制ACE的活性而达到降血压的作用。ACE抑制剂广泛用于治疗心血管、高血压、心力衰竭、肾衰竭等疾病。ACE抑制剂最初是从蛇毒中发现的,随后人们发现从食物原料中也可以提取ACE抑制肽,如明胶、酪蛋白、鱼、无花果树胶、α-玉米蛋白等都可作为制备ACE抑制肽的原料。但是这些ACE抑制肽的制备方法较复杂,也不能取得较为满意的抑制效果。
发明内容
有鉴于此,本发明的目的在于一种抑制血管紧张素转换酶活性的多肽,结构简单,在极低浓度下就能达到满意的ACE抑制效果。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了一种抑制血管紧张素转换酶活性的多肽,所述多肽的氨基酸序列如SEQ ID NO.1所示。
本发明还提供了所述多肽在制备降压药物中的应用。
本发明还提供了所述多肽在制备血管紧张素转换酶抑制剂中的应用。
本发明提供了一种抑制血管紧张素转换酶活性的多肽,所述多肽的氨基酸序列如SEQ ID NO.1所示(Pro-Gly-Asp-Arg-Asp-Asn-Leu,PGDRDNL)。本发明所述多肽针对ACE靶标均具有抑制活性,从而表现出同时具有降血压的特性。在本发明实施例中,对ACE抑制活性进行检测,发现1.0mg/mL时的ACE抑制活性为90.27%,2.0mg/mL时的ACE抑制活性为96.16%,因此所述多肽的活性与浓度存在量效关系,属于新的具ACE抑制活性功能肽。
附图说明
图1为本发明实施例中肽PGDRDNL的结构图。
具体实施方式
本发明提供了一种抑制血管紧张素转换酶活性的多肽,所述多肽的氨基酸序列如SEQ ID NO.1所示。
本发明所述多肽的氨基酸序列为Pro-Gly-Asp-Arg-Asp-Asn-Leu,也可缩写为PGDRDNL。本发明所述多肽优选来源于中华鳖甲鱼或人工合成,当来源于中华鳖甲鱼时,优选的将中华鳖甲鱼蛋白(GenBank:QBH72622.1,insulin-like growth factor bindingprotein 7,partial[Pelodiscus sinensis]),通过计算机辅助虚拟酶解技术,获得了在胃蛋白酶Pepsin(pH>2)的作用条件下,得到所述多肽。当来源于人工合成时,本发明实施例中选择吉尔生化(上海)有限公司合成。
本发明对所述多肽的结构并没有特殊限定,优选的还包括不同蛋白质来源降解分离所得的多肽PGDRDNL结构及其衍生化结构,更优选的如图1所示。
本发明还提供了所述多肽在制备降压药物中的应用。
在本发明所述应用中,所述降压药物优选口服药。本发明对所述口服药的剂型及制备方法并没有特殊限定,利用本领域的常规方法制备即可。本发明所述药物的服用量为1.0g所述多肽/次,每天服用2~3次。
本发明还提供了所述多肽在制备血管紧张素转换酶抑制剂中的应用。
在本发明所述应用中,所述抑制剂优选口服药。本发明对所述口服药的剂型及制备方法并没有特殊限定,利用本领域的常规方法制备即可。本发明所述抑制剂的服用量为1.0g所述多肽/次,每天服用2~3次。
下面结合实施例对本发明提供的一种抑制血管紧张素转换酶活性的多肽及其应用进行详细的说明,但是不能把它们理解为对本发明保护范围的限定。
实施例1
肽PGDRDNL在1.0mg/mL的浓度下的ACE抑制活性:
1、色谱条件:溶剂I为0.05%三氟乙酸(TFA)和0.05%的三乙胺(TTA)溶于去离子水中(即每升溶剂I中含有0.5mL的三氟乙酸和0.5mL的三乙胺),溶剂Ⅱ为100%的色谱纯乙睛。溶剂I与溶剂Ⅱ的比例为70%:30%(体积比),ultimate3000戴安液相色谱仪,色谱柱为waters Symmetry C18 5μm 4.6×250mm,流速为0.5mL/min,进样量10μL,检测波长为225nm,检测柱温为30℃。
2、检测方法:将通过化学合成法获得多肽PGDRDNL结构(图1),进行活性检测:
ACE在37℃,pH值为8.3的条件下催化分解血管紧张素I的模拟物Hippuryl-L-Histidyl-L-Leucine(HHL)产生马尿酸(HA),该物质在紫外225nm处具有特征吸收峰;当加入ACE抑制剂时ACE对HHL的催化分解作用受到抑制,马尿酸的生成量减少,通过HPLC方法,测定加入抑制剂前后所生成马尿酸的量的变化即可算出抑制活性的大小。
反应体系为:依次分别加入20μL 0.1U/mL的ACE、50μL ACE抑制肽(即GD二肽)在37℃温浴5min,然后加入10μL 5mM的HHL底物启动ACE的催化反应,在37℃振荡水浴30min后加入250μL 1.0mol/L的HCl终止反应,体系溶液过0.45μm滤膜后进行RP-HPLC检测分析马尿酸(HA)的含量。上述同样条件,以50μL 0.1mol/L的硼酸缓冲液中(含0.3mol/L的NaCl,pH=8.3)代替ACE抑制剂作为空白反应体系。
注:上述ACE、HHL底物均是以0.1mol/L的硼酸缓冲液(含0.3mol/L的NaCl,pH=8.3)为溶剂。
ACE抑制肽(PGDRDNL),以不同浓度溶解在0.1mol/L的硼酸缓冲液中(含0.3mol/L的NaCl,pH=8.3)中而得。
RP-HPLC检测:溶剂Ⅰ为0.05%(V/V)三氟乙酸(TFA)和0.05%(v/v)的三乙胺(TTA)溶于去离子水中,溶剂Ⅱ为100%的色谱纯乙睛。溶剂Ⅰ与溶剂Ⅱ的比例为70%:30%(体积比),流速为0.5mL/min,检测波长为225nm,检测柱温为30℃。
ACE抑制活性根据下式计算:
I%=(A-B)/A×100%
A:不加入短肽抑制剂时的马尿酸的峰面积;
B:加入短肽抑制剂时的马尿酸的峰面积;
ACE:1U单位定义为,在标准检测条件下,在37℃,1min时间内催化底物(Hippuryl-L-Histidyl-L-Leucine,HHL),产生1μM马尿酸所消耗ACE的量。即为ACE的活性单位。
3、结果:肽PGDRDNL在1.0mg/mL时的ACE抑制活性为90.27%。
实施例2
肽PGDRDNL在2.0mg/mL的浓度下的ACE抑制活性:
1、色谱条件:溶剂Ⅰ为0.05%三氟乙酸(TFA)和0.05%的三乙胺(TTA)溶于去离子水中;溶剂Ⅱ为100%的色谱纯乙睛。溶剂Ⅰ与溶剂Ⅱ的比例为70%:30%,ultimate3000戴安液相色谱仪,色谱柱为waters Symmetry C18 5μm 4.6×250mm,流速为0.5mL/min,进样量10μL,检测波长为225nm,检测柱温为30℃。
2、检测方法:将通过化学合成法获得此7肽结构,进行活性检测(检测方法同实施例1)。此时肽PGDRDNL浓度为2.0mg/mL。
3、结果:肽PGDRDNL在2.0mg/mL时的ACE抑制活性为96.16%。
本发明提供了一种抑制血管紧张素转换酶活性的多肽,针对ACE靶标均具有抑制活性,从而表现出同时具有降血压的特性;且多肽的活性与浓度存在量效关系,属于新的具ACE抑制活性功能肽,可将其用于制备ACE抑制剂或降压药物。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
序列表
<110> 浙江省农业科学院
<120> 一种抑制血管紧张素转换酶活性的多肽及其应用
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Pro Gly Asp Arg Asp Asn Leu
1 5
Claims (3)
1.一种抑制血管紧张素转换酶活性的多肽,其特征在于,所述多肽的氨基酸序列如SEQID NO.1所示。
2.权利要求1所述多肽在制备降压药物中的应用。
3.权利要求1所述多肽在制备血管紧张素转换酶抑制剂中的应用。
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