WO2019006951A1 - 非极性二肽在制备降血压药物或保健品中的应用 - Google Patents

非极性二肽在制备降血压药物或保健品中的应用 Download PDF

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WO2019006951A1
WO2019006951A1 PCT/CN2017/111643 CN2017111643W WO2019006951A1 WO 2019006951 A1 WO2019006951 A1 WO 2019006951A1 CN 2017111643 W CN2017111643 W CN 2017111643W WO 2019006951 A1 WO2019006951 A1 WO 2019006951A1
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dipeptide
ace
amino acid
use according
pharmaceutically acceptable
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潘武广
朱威
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广州世优生物科技有限公司
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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
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • 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
    • 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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  • the present invention relates to novel applications of dipeptides, and in particular to the use of dipeptides in the preparation of blood pressure lowering drugs or health care products.
  • Angiotensin converting enzyme is a zinc metalloproteinase, a carboxy dipeptidase, and one of the important proteases in the renin-angiotensin system. It plays an important role in the regulation of blood pressure in the human body. It removes His-Leu to produce angiotensin II by acting on the end of angiotensin I, which can cause arterial vascular smooth muscle to contract and rapidly cause blood pressure to rise. Inhibition of ACE activity is an effective method for lowering blood pressure. Most of the current drugs for the treatment of hypertension are chemical synthetic products, and there are some adverse reactions such as cough, dysfunction of the taste and rash.
  • the ACE inhibitory peptide prepared from the food-derived protein has the advantages of high safety, small toxic and side effects, and is an important direction for the development of antihypertensive drugs.
  • Short peptides are easy to prepare and have no side effects on the human body. Studies have shown that short peptides with specific structures, such as dipeptides, tripeptides, tetrapeptides, etc., have a certain inhibitory effect on the activity of ACE, and are a very promising ACE enzyme inhibitor.
  • angiotensin-converting enzyme dipeptide inhibitor was constructed by using molecular electro-negativity edge vector (MEEV) as a parameter and 36 angiotensin-converting enzyme dipeptide inhibitors as samples.
  • MEEV molecular electro-negativity edge vector
  • the "two, five, seven" bond of the dipeptide peptide bond inhibits the activity of the enzyme, that is, (1) the carboxyl group of the peptide bond and the Zn form a diligand, and the N atom of the peptide bond and the carboxyl group form H bond to stabilize this group; (2) buckling with a five-bond structural unit formed between the carboxylate of the positively charged salt of Arg (Arginine, arginine) and the amino group of the second amino acid in the ACE enzyme The effect plays a key role; (3) The amino group of the peptide bond in the dipeptide inhibitor containing aromatic amino acid and the hydroxy terminal of the benzene ring are in a trans configuration, which are separated by 7 bonds.
  • ACE inhibits dipeptide
  • the correlation coefficient, cross-validation correlation coefficient, root mean square error and external verification correlation coefficient of the model were 0.851, 0.781, 0.327, and 0.792, respectively; the tripeptide models were 0.805, 0.717, 0.339, and 0.817, respectively; the tetrapeptide models were 0.792 and 0.553, respectively. , 0.393, 0.630.
  • the strong hydrophobicity and weak charge property of the C-terminal amino acid residue have a positive effect on its activity;
  • the hydrophobicity, electrical characteristics, steric characteristics and steric characteristics of the N-terminal amino acid residues of the terminal amino acid residues are highly correlated with the peptide activity.
  • a dipeptide having a non-polar acyclic amino acid at the N-terminus especially a dipeptide AC, AK, AT, IA, IC, IE, IH, II, IK, IL, IM, IN, IQ, IS, IT, IV LD, LE, LH, LI, LK, LM, LQ, LT, LV, VI, VK, VM, VT have good ACE inhibitory activity.
  • amino acid in the dipeptide is L-form or D-form, and at least one amino acid in the dipeptide is optionally modified to have a group which enhances the stability of the dipeptide in vivo.
  • Dipeptides also include simple derivatives thereof that are pharmaceutically acceptable.
  • Simple derivatives include, but are not limited to, pharmaceutically acceptable salts of dipeptides, pharmaceutically acceptable esters.
  • Pharmaceutically acceptable salts include, but are not limited to, potassium, calcium, sodium, zinc, iron, and ferrous salts.
  • Pharmaceutically acceptable esters include, but are not limited to, C2 to C10 pharmaceutically acceptable esters.
  • Dipeptides can also be used to prepare ACE enzyme inhibitors, particularly experimental ACE enzyme inhibitors.
  • the dipeptide of the invention can inhibit the activity of ACE well and has a good blood pressure lowering effect, and is particularly suitable for development. Health care products for lowering blood pressure.
  • the combination of two or more dipeptides is expected to achieve better results.
  • the mixture was mixed and placed on a SpectraMax microplate reader. At 37 ° C, 340 nm was used as the main wavelength and 405 nm was used as the reference wavelength. The change in absorbance value was detected and continuously monitored for 1 hour to draw a kinetic curve.
  • the synthesized dipeptide sample was dissolved in ultrapure water, and a 20 mg/mL stock solution was placed, and then diluted to a sample having a concentration of 20 ⁇ g/mL as a sample.
  • FAPGG reagent 200 200 200 200 200 200 200 200 115u/L ACE ( ⁇ l) 20 20 20 20 20 - 20 ⁇ g/mL dipeptide ( ⁇ l) 20 - - - - - - Captopril ( ⁇ l) - 4 20 20 - - Ultrapure water ( ⁇ l) 0 16 0 0 20 40
  • the dipeptide of the present invention can inhibit the activity of ACE well, has a good blood pressure lowering effect, and is particularly suitable for development as a health care product for lowering blood pressure.
  • the combination of two or more dipeptides is expected to achieve better results.

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Abstract

一种二肽在制备降血压药物或保健品中的应用。根据已经测定的ACE酶晶体结构，采用分子对接法，利用自研软件对二肽的ACE抑制作用进行虚拟筛选，并对虚拟筛选得到的二肽的ACE抑制活性进行实验验证。发现非极性无环结构氨基酸开头的二肽具有较好的ACE抑制活性。

Description

非极性二肽在制备降血压药物或保健品中的应用 技术领域
本发明涉及二肽的新应用，特别涉及二肽在制备降血压药物或保健品中的应用。
背景技术
血管紧张素转化酶(Angiotensin converting enzyme，ACE)是一种锌金属蛋白酶，是羧基二肽酶，是肾素-血管紧张素系统中重要的蛋白酶之一。对人体血压调节有着重要的作用，通过作用于血管紧张素I的末端去掉His-Leu生成血管紧张素Ⅱ，它能够使动脉血管平滑肌收缩，迅速引起血压上升。抑制ACE活性是一种使血压下降的有效的方法。当前治疗高血压的药物大多是化学合成品，存在一些不良反应，如咳嗽、味觉功能紊乱及皮疹等副作用。食源性蛋白为原料制得的ACE抑制肽由于具有安全性高、毒副作用小等优点，是降压药物研发的重要方向。
短肽易于制备，对人体基本无副作用。研究表明具有特定结构的短肽，如二肽、三肽、四肽等对ACE的活性有一定抑制作用，是一种非常具有开发前景的ACE酶抑制剂。
刘焕，乐国伟，施用晖，等.血管紧张素转化酶二肽抑制剂的构效关系[J].计算机与应用化学，2006，22(8):631-635.中公开了从肽链的一级结构出发，以分子电边矢量(molecular electro-negativity edge vector，MEEV)为参数，36种血管紧张素转化酶二肽抑制剂为样本，构建了血管紧张素转化酶二肽抑制剂的构效关系模型。通过模型分析得出二肽肽键的“二、五、七”键抑制酶活的规律，即:(1)肽键的羧基和Zn形成二配体，而肽键的N原子和羧基氧形成H键以稳定这一基团；(2)与ACE酶中Arg(Arginine，精氨酸)正电荷盐键作用的羧酸根和第二氨基酸的氨基之间形成的五键结构单元对其降压效果起关键作用；(3)含芳香族氨基酸的二肽抑制剂中的肽键的氨基和苯环部分羟基端呈反式构型，它们相隔7个键位。
刘静，彭剑秋，管骁.基于多元线性回归的血管紧张素转化酶抑制肽定量构效关系建模研究[J].分析科学学报，2012，28(001):16-22.公开了利用氨基酸结构描述符SVHEHS分别对血管紧张素转化酶(Angiotensin converting Enzyme，ACE)竞争性抑制二肽、三肽、四肽序列表征后，建立结构与活性的多元线性回归(MLR)模型.ACE抑制二肽模型的相关系数、交叉验证相关系数、均方根误差、外部验证相关系数分别为0.851、0.781、0.327、0.792；三肽模型分别为0.805、0.717、0.339、0.817；四肽模型分别为0.792、0.553、0.393、0.630.
刘焕.大米ACE抑制肽的研究[D].江南大学，2005.以分子电边矢量(molecular electro- negativity edge vector，MEEV)为参数，36种血管紧张素转化酶二肽抑制剂为样本，构建了血管紧张素转化酶二肽抑制剂的构效关系模型。通过模型分析表明C末端的疏水性氨基酸如芳香族氨基酸和支链氨基酸是影响ACE抑制活性的关键因素。
刘静，管骁，彭剑秋.基于氨基酸描述符SVHEHS的ACE抑制肽QSAR研究[J].化学学报，2012，70(1):83-91.公开的研究结论显示二肽C端氨基酸的疏水性(X15)、电性(X17)、立体特征(X24)和N端氨基酸的立体特征(X12)与肽活性相关性较大。
彭剑秋.ACE抑制肽定量构效关系研究[D].上海理工大学，2012.公开的结果表明二肽模型R2＝0.851，RMSE＝0.327，Q2LOO＝0.781，Q2ext＝0.792，且C端氨基酸残基疏水性质及电荷性质和N端氨基酸残基立体特征对ACE抑制二肽的活性影响较大，特别是C端氨基酸残基强的疏水性和弱的电荷性质对其活性有积极作用；C端氨基酸残基的疏水性、电性特征、立体特征和N端氨基酸残基的立体特征与肽活性相关性较大。
现有技术从多角度对短肽对ACE活性抑制进行了研究，试图确定短肽结构与ACE抑制活性之间关系，但是现有的研究结果都具有其局限性，预测结果的准确性不高，未能发现具有高ACE抑制活性的二肽。
开发出具有高ACE抑制活性的二肽，具有非常实际的意义。
发明内容
本发明的目的在于提供二肽在制备降血压药物或保健品中的应用。
本发明所采取的技术方案是：
本发明根据已经测定的ACE酶晶体结构，采用分子对接法，利用自研软件对400种二肽的ACE抑制作用进行虚拟筛选，并对虚拟筛选得到的二肽的ACE抑制活性进行实验验证。发现N端为非极性无环结构氨基酸的二肽，特别是二肽AC、AK、AT、IA、IC、IE、IH、II、IK、IL、IM、IN、IQ、IS、IT、IV、LD、LE、LH、LI、LK、LM、LQ、LT、LV、VI、VK、VM、VT，具有很好的ACE抑制活性。
进一步的，二肽中的氨基酸为L型或D型，二肽中的至少一个氨基酸上可选修饰有提高二肽在体内稳定性的基团。
二肽还包括其药学上可接受的简单衍生物。简单衍生物包括但不限于二肽的药用盐、药用酯。药用盐包括但不限于钾、钙、钠、锌、铁、亚铁盐。药用酯包括但不限于C2～C10的药用酯。
二肽还可以用于制备ACE酶活抑制剂，特别是实验用ACE酶活抑制剂。
本发明的二肽，可以很好地抑制ACE的活性，具有较好的降血压作用，特别适合开发成 为降血压的保健品。二种或更多种二肽组合使用，有望获得更佳的效果。
具体实施方式
ACE酶活检测
不同ACE酶量的动力学曲线
配置反应如下表：
编号 1 2 3 4 5 6
FAPGG试剂(μl) 200 200 200 200 200 200
115u/L ACE(μl) 20 16 12 8 4 0
超纯水(μl) 20 34 28 32 36 40
备注:酶活 115u/L 92u/L 69u/L 43u/L 23u/L 0u/L
混匀，置于SpectraMax酶标仪上，于37℃下，以340nm为主波长，405nm为参比波长，检测吸光度值的变化，连续监测1小时，绘制动力学曲线。
二肽对ACE抑制效果采用如下方法测试得到：
用超纯水溶解合成的二肽样本，配置20mg/mL原液，然后稀释成20μg/mL浓度的样品作为试样。
编号 1 2 3 4 5 6
FAPGG试剂(μl) 200 200 200 200 200 200
115u/L ACE(μl) 20 20 20 20 20 -
20μg/mL二肽(μl) 20 - - - - -
卡托普利(μl) - 4 20 20 - -
超纯水(μl) 0 16 0 0 20 40
混匀，置于SpectraMax酶标仪上，于37℃下，以340nm为主波长，405nm为参比波长，检测吸光度值的变化，连续监测1小时。计算酶促动力学曲线中，直线段的斜率，根据式(1)计算样品的抑制率
Figure PCTCN2017111643-appb-000001
其中
Figure PCTCN2017111643-appb-000002
E—样品孔的ACE酶活U/L)
Ss—样品孔ACE动力学曲线直线段的斜率
Sp—未加抑制剂孔的ACE动力学曲线直线段的斜率
Sb—空白孔ACE动力学曲线直线段的斜率。
AC、AK、AT、IA、IC、IE、IH、II、IK、IL、IM、IN、IQ、IS、IT、IV、LD、LE、LH、LI、LK、LM、LQ、LT、LV、VI、VK、VM、VT的计算结果和抑制率如下：
Figure PCTCN2017111643-appb-000003
从实验数据可以确定，本发明的二肽可以很好地抑制ACE的活性，具有较好的降血压作用，特别适合开发成为降血压的保健品。二种或更多种二肽组合使用，有望获得更佳的效果。

Claims (11)

  1. 二肽在制备降血压药物或保健品中的应用，其特征在于：所述二肽的N端为非极性无环结构氨基酸，二肽中的氨基酸为L型或D型。
  2. 根据权利要求1所述的应用，其特征在于：二肽选自AC、AK、AT、IA、IC、IE、IH、II、IK、IL、IM、IN、IQ、IS、IT、IV、LD、LE、LH、LI、LK、LM、LQ、LT、LV、VI、VK、VM、VT，二肽中的氨基酸为L型或D型。
  3. 根据权利要求1或2所述的应用，其特征在于：二肽中的至少一个氨基酸上可选修饰有提高二肽在体内稳定性的基团。
  4. 根据权利要求1或2所述的应用，其特征在于：二肽还包括其药学上可接受的简单衍生物。
  5. 根据权利要求4所述的应用，其特征在于：简单衍生物为二肽的药用盐、药用酯。
  6. 根据权利要求5所述的应用，其特征在于：药用盐为钾、钙、钠、锌、铁、亚铁盐。
  7. 根据权利要求5所述的应用，其特征在于：药用酯为C2～C10的药用酯。
  8. 二肽在制备ACE酶活抑制剂中的应用，其特征在于：所述二肽的N端为非极性无环结构氨基酸，二肽中的氨基酸为L型或D型。
  9. 根据权利要求8所述的应用，其特征在于：二肽选自AC、AK、AT、IA、IC、IE、IH、II、IK、IL、IM、IN、IQ、IS、IT、IV、LD、LE、LH、LI、LK、LM、LQ、LT、LV、VI、VK、VM、VT，二肽中的氨基酸为L型或D型。
  10. 根据权利要求8或9所述的应用，其特征在于：ACE酶活抑制剂为实验用ACE酶活抑制剂。
  11. 一种降血压药物或保健品，其特征在于：其含有权利要求1～7任一项所述二肽中的至少2种。
PCT/CN2017/111643 2017-07-07 2017-11-17 非极性二肽在制备降血压药物或保健品中的应用 WO2019006951A1 (zh)

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