CN1994464A - 一种血管紧张素i转换酶抑制剂及其应用 - Google Patents
一种血管紧张素i转换酶抑制剂及其应用 Download PDFInfo
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Abstract
本发明涉及血管紧张素I转换酶抑制剂及其应用,其具有序列表SEQID NO:1中氨基酸序列。本发明应用现代分子生物技术对珠蛋白进行酶解,对具有ACE抑制活性较强的部分进行分离纯化,对纯化得到的肽进行氨基酸序列分析,并研究了此肽在体内对ACE的抑制活性,结果表明此肽有很好的降血压效果。因此,可以将此活性肽及其衍生物或者其盐类作为高血压患者的长期治疗药物,或者作为食品添加剂制成保健食品。
Description
技术领域
本发明涉及血管紧张素I转换酶抑制剂,一种血管紧张素I转换酶抑制肽以及它的类似物,或者其盐类中的一种所构成的ACE抑制剂。
背景技术
高血压是最常见的心血管疾病之一,它能造成大脑、心血管、肾脏的损害,是引起脑卒中、心力衰竭和冠心病等的重要因素,严重威胁着人类的健康。因此,治疗和预防高血压对提高人类的健康水准,延长寿命有着重要的意义。
血管紧张素I转换酶(ACE)在人体肾素-血管紧张素系统和激肽释放酶-激肽系统中,对血压调节起着重要的作用。ACE可以将血管紧张素I转换为血管紧张素II,使周围小动脉、血管平滑肌收缩,同时刺激醛固酮分泌,促进人体肾脏对Na+、K+的重吸收,引起钠储量和血容量的增加,使血压升高;还可以使舒缓激肽失活,引起血压升高。
综上所述,ACE一方面产生使血压上升的血管紧缩素II,另一方面,使具有血管舒张作用的舒缓激肽失活,这都造成了血压的上升。所以,如果抑制了ACE的活性,就可以起到降压的作用。
现有的作为治疗高血压的合成物卡普托利就是ACE的抑制剂,但它有很多副作用,所以源于食品蛋白中的ACE抑制肽因其无毒副作用,同时具有其它疗效而被广泛应用,市场前景极好。
发明内容
本发明提供一种来源于食品的、高安全性的、廉价的、可产业化生产的血管紧张素I转换酶ACE抑制剂及其应用。
为实现上述目的,本发明采用的技术方案为:
一种血管紧张素I转换酶抑制剂,其具有序列表SEQ ID NO:1中氨基酸序列。
其是从珠蛋白的胃蛋白酶水解液中经过一系列分离、纯化获得的活性单肽,高效毛细管电泳鉴定纯度大于95%,基体辅助激光解吸/电离飞行时间质谱(MALDI-MS)和电喷雾串联质谱(ESI-MS/MS)测定此活性肽的分子量为1554道尔顿,其氨基酸序列为Leu-Gly-Phe-Pro-Thr-Thr-Lys-Thr-Tyr-Phe-Pro-His-Phe(LGFPTTKTYFPHF),它对ACE有很好的抑制作用;由氨基酸璇光度不同而定义为L型氨基酸和D型氨基酸所形成的不同构型的十三肽。
所述抑制剂为活性单肽,其活性单肽或与单肽同源性80%以上的衍生物可用于制备治疗和预防高血压的药物。
所述抑制剂活性单肽或与单肽同源性80%以上的衍生物可按常规方法生成它们相应的盐,其盐可用于制备治疗和预防高血压的药物。
上述肽及与单肽同源性80%以上的衍生物的盐类可以用通常的方法生产。公认的与酸反应产生的盐类,比如说盐酸,硫酸,硝酸,磷酸等无机酸;蚁酸,乙酸,丙酸,甘氨胆酸,苹果酸,柠檬酸,酒石酸,琥珀酸等有机酸等形成的盐类;公认的与金属离子形成的盐类,包括钠盐,钾盐,钙盐,铵盐;以及氨基乙醇,三乙氨,二环乙氨等形成的胺类盐等没有特别的限制。
所述药物的剂型可为单肽或与单肽同源性80%以上的衍生物,及其盐与充填剂所形成的各种形式的散剂,颗粒剂,片剂,胶囊,水溶液,悬浮液,乳化液,喷剂或粉剂等,通过口腔摄取或者是注射液的形式使用;使用量是没有特别的限制,具体的要根据高血压的程度,患者的年龄,体重,身体状况和给与的方法等因素,适当地确定;药物可制成各种制剂,其使用时可以采取经口腔或非经口腔的投入方法;非经口腔的投入可以采取皮下注射、静脉注射、或肛肠投入等;注射液的制作可以任意选用生理盐水、葡萄糖、安定剂、防腐剂、悬浮剂或乳化剂等。
所述活性单肽,其活性单肽或与单肽同源性80%以上的衍生物、或它们相应的盐,可以添加到各种食品当中,制成抑制血压的保健食品;食品的形态可以是清凉饮料,乳酸饮料,调味品,汤类,奶酪,火腿,点心等。
本发明具有如下优点:
1.廉价、可产业化生产。本发明原料来源广泛,分离方法简单,成本低。
2.应用效果好。本发明应用现代分子生物技术对珠蛋白进行酶解,对具有ACE抑制活性较强的部分进行分离纯化,对纯化得到的肽进行氨基酸序列分析;并研究了此肽在体内对ACE的抑制活性,其主要作用于肾素-血管紧缩素系统中的血管紧缩素I转换酶(angiotensin I coverting enzyme,略称为ACE),抑制了它的活性,阻止了血管紧缩素I转换成血管紧缩素II,结果表明此肽有很好的降血压效果。本发明活性单肽或与单肽同源性80%以上的衍生物、或它们相应的盐中的任意一种成份均作为血管紧缩素I转换酶抑制剂。从而可以降低动物血压,或者抑制动物血压的升高趋势。
3.来源于动物食品、高安全性。可以将本发明活性肽及其衍生物、或它们的盐类作为高血压患者的长期治疗药物,或者作为食品添加剂制成保健食品。
附图说明
图1为珠蛋白酶解液用Sephadex G-25柱子洗脱时的洗脱曲线;
图2为珠蛋白酶解液在RP-HPLC上的洗脱曲线;
图3为静脉注射不同剂量的抑制剂后高血压大鼠的收缩压变化随时间变化曲线。
具体实施方式
下面结合实施例对本发明作进一步的阐述:
实施例1
一种血管紧张素I转换酶抑制剂,具有序列表SEQ ID NO:1中氨基酸序列;
其氨基酸序列为Leu-Gly-Phe-Pro-Thr-Thr-Lys-Thr-Tyr-Phe-Pro-His-Phe(LGFPTTKTYFPHF);
(1)SEQ ID No:1的信息(参见序列表)
(a)序列特征
*长度:13aa
*类型:肽
*链型:直链
*拓扑结构:线性
(b)分子类型:PRT
(C)最初来源:猪的血红蛋白(porcine hemoglobin)的α-chain(34-46)。
其制备过程如:
按常规方法进行血红素的分离:新鲜猪血加0.8%的柠檬酸三钠(防止血液凝集),搅拌均匀后,3000r/min离心,取血球(沉淀部分)加等量的蒸馏水,搅拌30分钟后,血球溶血,加5倍体积的含3%HCl的丙酮溶液,搅拌静置后,过滤,取沉淀部分,喷雾干燥后即得珠蛋白粉末。(参考文献:周淡宜,徐水祥,周敏子.血红素制备工艺的实验研究.药物生物技术.2002,9(2):103-104.)
称取珠蛋白粉末3g溶于100ml的磷酸缓冲液中,加入1%(酶与底物比)的胃蛋白酶,在37℃和pH2的条件下酶解12小时,反应结束后,在100℃下加热10min,终止酶解,用NaOH溶液调节酶解液成中性;将酶解液经过截留率为10kDa分子量的膜超滤后,经真空浓缩仪浓缩至20ml,将20ml浓缩液通过Sephadex G-25凝胶过滤柱进行分离,每20分钟接收一管,每管在波长为280nm下检测吸光度,得到如图1的洗脱曲线,由图知,分离得到五个部分,将每一部分混合在一起冷冻干燥,然后对这五个部分分别进行对ACE抑制活性的测定,这五部分在相同的浓度下对ACE的抑制率五区最大,所以对5区在RP-HPLC上进行进一步的分离,在RP-HPLC上用Hypersil C18柱,流动相A液为:0.1%TFA+0%乙腈的水溶液,用前超声脱气;流动相B液为:0.1%TFA+100%乙腈的水溶液,检测波长215nm,室温,进样体积20μl,采用梯度洗脱,按时间收集;洗脱梯度:0-60min:A液100%-50%线性降低,B液0%-50%线性升高;60-80min:A液0%,B液100%。
如图2所示,其中得到A组分有很好的ACE抑制活性,然后对A组分用基体辅助激光解吸/电离飞行时间质谱(MALDI-MS)和电喷雾串联质谱(ESI-MS/MS)进行分析,测定此活性肽的分子量为1554道尔顿,其氨基酸序列为Leu-Gly-Phe-Pro-Thr-Thr-Lys-Thr-Tyr-Phe-Pro-His-Phe(LGFPTTKTYFPHF),来源于猪的血红蛋白的α-chain 34-46
实施例2 动物实验
选择自发性高血压大鼠为实验模型,大鼠饲养一周后,将其分组,每组八只,用50-200mg/kg剂量的纯肽静脉注射,采用尾部测压的方法每隔30分钟测量一次血压,一直测到180分钟。
如图3所示,结果表明,用50mg/kg的剂量注射30分钟后对照组大鼠的血压保持172±5mm Hg,而治疗组自发性高血压大鼠的血压从172±5mmHg降至150±6mm Hg明显下降,下降了21.9±3.3mm Hg,最大抑制效果出现在60分钟后,血压降到最低(146±5.7mm Hg)。用50mg/kg、100mg/kg、200mg/kg的剂量用同样的大鼠只数和同样的方法进行实验,结果表明随着注射量的增加,血压的降低呈剂量依赖关系(如图所示)。由此可知此肽具有很好的降血压效果。
紧张素I
SEQUENCE LISTING
<110>中国科学院大连化学物理研究所
<120>一种血管紧张素I转换酶抑制剂及其应用
<130>
<160>1
<170>PatentIn version 3.1
<210>1
<211>13
<212>PRT
<213>猪的血红蛋白(porcine hemoglobin)
<220>
<221>CHAIN
<222>(1)..(13)
<223>
<400>1
Leu Gly Phe Pro Thr Thr Lys Thr Tyr Phe Pro His Phe
1 5 10
Claims (9)
1.一种血管紧张素I转换酶抑制剂,其特征在于:具有序列表SEQ IDNO:1中氨基酸序列。
2.一种权利要求1所述血管紧张素I转换酶抑制剂的应用,其特征在于:权利要求1所述抑制剂为活性单肽,其活性单肽或与单肽同源性80%以上的衍生物用于制备治疗和预防高血压的药物。
3.按照权利要求2所述血管紧张素I转换酶抑制剂的应用,其特征在于:所述抑制剂活性单肽或与单肽同源性80%以上的衍生物可按常规方法生成它们相应的盐,其盐可用于制备治疗和预防高血压的药物。
4.按照权利要求3所述血管紧张素I转换酶抑制剂的应用,其特征在于:所述盐为活性单肽或与单肽同源性80%以上的衍生物与酸反应产生的盐,或它们与金属离子形成的盐,或与氨基乙醇、三乙或二环乙氨反应形成的胺类盐。
5.按照权利要求3所述血管紧张素I转换酶抑制剂的应用,其特征在于:所述酸为盐酸、硫酸、硝酸、磷酸、蚁酸、乙酸、丙酸、甘氨胆酸、苹果酸、柠檬酸、酒石酸或琥珀酸;与金属离子形成的盐为钠盐、钾盐、钙盐或铵盐。
6.按照权利要求2或3所述血管紧张素I转换酶抑制剂的应用,其特征在于:所述药物的剂型可为单肽或与单肽同源性80%以上的衍生物及其盐与充填剂所形成的各种形式的颗粒剂,片剂,胶囊,水溶液,悬浮液,乳化液,喷剂或粉剂。
7.按照权利要求2或3所述血管紧张素I转换酶抑制剂的应用,其特征在于:所述药物可制成各种制剂,其使用时可以采取经口腔或非经口腔的投入方法;非经口腔的投入可以采取皮下注射、静脉注射、或肛肠投入;注射液的制作可以任意选用生理盐水、葡萄糖、安定剂、防腐剂、悬浮剂或乳化剂。
8.一种权利要求1所述血管紧张素I转换酶抑制剂的应用,其特征在于:权利要求1所述抑制剂为活性单肽,其活性单肽或与单肽同源性80%以上的衍生物、或它们相应的盐,可以添加到各种食品当中,制成抑制血压的保健食品。
9.按照权利要求8所述血管紧张素I转换酶抑制剂的应用,其特征在于:食品的形态可以是液体的清凉饮料、乳酸饮料、调味品或汤类,也可以是固体的奶酪、火腿或点心。
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CN111087446A (zh) * | 2019-12-30 | 2020-05-01 | 中新国际联合研究院 | 一种抑制血管紧张素转换酶的十肽及其应用 |
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CN111087446A (zh) * | 2019-12-30 | 2020-05-01 | 中新国际联合研究院 | 一种抑制血管紧张素转换酶的十肽及其应用 |
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