WO2016023150A1 - 二肽作为ace酶活性抑制剂的应用 - Google Patents

二肽作为ace酶活性抑制剂的应用 Download PDF

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WO2016023150A1
WO2016023150A1 PCT/CN2014/084089 CN2014084089W WO2016023150A1 WO 2016023150 A1 WO2016023150 A1 WO 2016023150A1 CN 2014084089 W CN2014084089 W CN 2014084089W WO 2016023150 A1 WO2016023150 A1 WO 2016023150A1
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dipeptide
amino acid
ace
activity
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贺雄雷
朱威
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WITHYOU BIOTECHNOLOGY Co Ltd
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Priority to US15/503,328 priority patent/US10441624B2/en
Priority to EP14899664.8A priority patent/EP3219324B1/en
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/556—Angiotensin converting enzyme inhibitors
    • 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

Definitions

  • the present invention relates to novel applications of dipeptides, and in particular to the use of dipeptides as inhibitors of ACE enzyme activity.
  • Angiotensin converting enzyme is a zinc metalloproteinase, a carboxydipeptidase, 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 contraction and rapidly cause blood pressure to rise. Inhibition of ACE activity is an effective method for lowering blood pressure. Most of the drugs currently used to treat high blood pressure are chemically synthesized products, and there are some adverse reactions such as cough, dysfunction of the taste and rash. The ACE inhibitory peptide prepared from food-derived protein is an important direction for the development of antihypertensive drugs because of its high safety and small side effects.
  • 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 promising ACE enzyme inhibitor.
  • angiotensin-converting enzyme II was constructed by using molecular electro-negativity edge (Molecular electro-negativity edge ⁇ 6 01 ⁇ £ ⁇ ) as a parameter and 36 angiotensin-converting enzyme dipeptide inhibitors as samples.
  • molecular electro-negativity edge Molecular electro-negativity edge ⁇ 6 01 ⁇ £ ⁇
  • the "two, five, seven" bond of the dipeptide peptide bond inhibits the activity of the enzyme, namely: (1) the carboxyl group of the peptide bond and the Zn form a diligand, and the N bond of the peptide bond and the carboxyl group form The H bond stabilizes this group; (2) the five-bond structural unit formed between the carboxylate of the positively charged salt bond of Arg (Argini ne , arginine) and the amino group of the second amino acid in the ACE enzyme The pressure 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 inhibiting dipeptide model The correlation coefficient, cross-validation correlation coefficient, root mean square error, and external verification correlation coefficient 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 properties of the C-terminal amino acid residues 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.
  • the ACE inhibitory effect of 400 dipeptides is virtually screened by molecular docking method, and the ACE inhibitory activity of the dipeptide obtained by the virtual screening is experimentally verified. It was found that when the N-terminal of the dipeptide is cysteine, the dipeptide has a good ACE inhibitory activity; when the C-terminal amino acid of the dipeptide is selected from a basic amino acid or an aliphatic amino acid, the dipeptide has a better ACE. Inhibitory activity, in particular, when the basic amino acid is selected from H, K, the aliphatic amino acid is selected from ruthenium, I has excellent ACE inhibitory activity.
  • the 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.
  • a dipeptide for inhibition of ACE enzyme activity is cysteine, the amino acid in the dipeptide is L-form or D-form, and at least one amino acid in the dipeptide is optionally modified to enhance dipeptide in vivo. a stable group.
  • the C-terminal amino acid of the dipeptide is selected from the group consisting of a basic amino acid or an aliphatic amino acid.
  • the basic amino acid selection ⁇ ⁇ , ⁇ , aliphatic amino acids are selected from ⁇ , I.
  • the beneficial effects of the invention are:
  • the dipeptide of the present invention can inhibit the activity of ACE well, and the inhibition rate of ACE is more than 30% at a concentration of 20 g/ml, and the inhibitory activity far exceeds the existing dipeptide, and has excellent development potential.
  • Figure 1 is a power curve for different amounts of ACE enzymes
  • Figure 2 is a plot of the slope of the straight line segment of the kinetic curve versus enzyme activity
  • Figure 3 is a captopril inhibition curve for ACE.
  • kinetic curves of different ACE enzyme amounts are shown in Fig. 1.
  • the relationship between the slope of the linear section of the kinetic curve and the enzyme activity is shown in Fig. 2.
  • the results show that the slope of the straight line segment of the kinetic curve is linear with the ACE activity.
  • Ultrapure water (; ⁇ 1) 0 4 8 12 16 20 Mix and place on a SpectraMax microplate reader, at 37 ° C, with 340 nm as the main wavelength and 405 nm as the reference wavelength. Detect the change in absorbance value continuously. Monitor for 1 hour.
  • the captopril inhibition curve is shown in Figure 3. As can be seen from Fig. 3, as the overall trend shows, as the concentration of captopril decreases, the inhibition rate decreases. In the experiment, the linear concentration was used, so the magnitude of the change in the inhibition rate was reduced.
  • the synthesized dipeptide sample was dissolved in ultrapure water, and a 20 mg/mL stock solution was placed, and then diluted to a sample of 20 g/mL as a sample.

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Abstract

一种二肽作为ACE酶活性抑制剂的应用。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，发现当二肽的N端为半胱氨酸时，二肽具有较好的ACE抑制活性。

Description

二肽作为 ACE酶活性抑制剂的应用 技术领域
本发明涉及二肽的新应用， 特别涉及二肽作为 ACE酶活性抑制剂的应用。
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 ¥6 01 ^£¥)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 (Angiotensinlconverting 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 PC15)、 电性 (Χ17)、 立体特征 (Χ24)和 Ν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作为 ACE酶活性抑制剂的应用。
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。 发现当二肽的 N端为半胱氨酸时， 二肽具有较好的 ACE抑制活性； 当二肽的 C端氨基酸选 自碱性氨基酸或脂肪族类氨基酸时， 二肽具有更好的 ACE抑制活性， 特别的， 当碱性氨基酸 选自 H、 K， 脂肪族类氨基酸选自 Α、 I时具有极好的 ACE抑制活性。
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。
用于 ACE酶活性抑制的二肽，二肽的 N端为半胱氨酸，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。
优选的， 二肽的 C端氨基酸选自碱性氨基酸或脂肪族类氨基酸。 特别的， 碱性氨基酸选 § Η、 Κ， 脂肪族类氨基酸选自 Α、 I。
本发明的有益效果是： 本发明的二肽， 可以很好地抑制 ACE的活性， 20 g/ml的浓度下， 对 ACE的抑制率达 30%以上， 抑制活性远超现有的二肽， 具有极好地开发潜力。
附图说明
图 1是不同 ACE酶量的动力曲线；
图 2是动力学曲线直线段斜率与酶活的关系曲线；
图 3是 ACE的卡托普利抑制曲线。
具体实施
下面结合实验， 进一步说明本发明的技术方案。
ACE酶活棚
不同 ACE酶量的动力学曲线
配置反应如下表：
Figure imgf000004_0001
混匀， 置于 SpectraMax酶标仪上， 于 37°C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。
不同 ACE酶量的动力学曲线如图 1所示，动力学曲线直线段斜率与酶活的关系曲线如图 2所示。 结果显示动力学曲线直线段斜率与 ACE酶活呈线性关系， 回归方程 y = -7*10_6x + 5*10— 5,R2=0.995。
不同卡托普利浓度对 ACE的抑制效果
用超纯水配置 2mg/mL卡托普利， 用超纯水进行 10倍比稀释， 至 10_8倍。
配置如下表反应体系
编号 1 2 3 4 5 6
FAPGG试剂（ μ
200 200 200 200 200 200
1) 115 u/LACE(
20 20 20 20 20 20
1)
2 μ g/L卡托普
20 16 12 8 4 0
利（μ ΐ)
超纯水 (； μ 1) 0 4 8 12 16 20
编号 1 2 3 4 5 6
FAPGG试剂（ μ
200 200 200 200 200 200
1)
115 u/LACE(
20 20 20 20 20 20
1)
0.2 μ g/L卡托普
20 16 12 8 4 0
利（μ ΐ)
超纯水 (； μ 1) 0 4 8 12 16 20 混匀， 置于 SpectraMax酶标仪上， 于 37°C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。
卡托普利抑制曲线如图 3所示。 由图 3可知， 整体趋势看， 随着卡托普利的浓度降低， 抑制率下降。 在实验中， 采用的是线性浓度， 故抑制率的变化幅度减小。
二肽对 ACE抑纖果
用超纯水溶解合成的二肽样本， 配置 20mg/mL原液， 然后稀释成 20 g/mL浓度的样 品作为试样。
Figure imgf000005_0001
混匀， 置于 SpectraMax酶标仪上， 于 37°C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 其中 E = 1 15
sp ~sb
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
实验结果如下表所示：
编号 二肽 抑制率 （％)
3 FE 6.18
5 KW 16.42
9 IF 18.35
11 KY 11.54
13 AY 8.18
15 KP 7.88
19 WL 7.27
20 KA 6.45
22 AG 3.08
25 CA 84.38
28 CH 70.79
29 CI 67.52
30 CK 38.39
38 DE 15.16
47 EV 14.26
48 EW 9.91
49 FD 5.05
50 FH 10.06
51 FI 9.58
55 FQ 10.96
57 FT 1.92 编号 二肽 抑制率 （％)
58 FW 3.16
59 GC 0.12
64 GT -3.20
65 HC 5.06
66 HD 10.98
67 HE 9.95
Capl 86.95
Cap2 72.84
Cap3 35.84
由表可知， 当二肽的 N端为半胱氨酸时， 二肽对 ACE的抑制率显著高于其他二肽， 特 别的， 当二^ ^为 CA、 CH、 CI、 CK时， 其抑制率更高。

Claims

权 利 要 求
1. 二肽作为 ACE酶活性抑制剂的应用， 其特征在于： 所述二肽的 N端为半胱氨酸， 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。
2. 根据权利要求 1所述的应用， 其特征在于： 二肽的 C端氨基酸选自碱性氨基酸或脂肪族 类氨基酸。
3. 根据权利要求 2所述的应用， 其特征在于： 所述碱性氨基酸选自 H、 K。
4. 根据权利要求 2所述的应用， 其特征在于： 所述脂肪族类氨基酸选自 Α、 I。
5. 作为 ACE酶活性抑制剂的二肽，所述二肽的 N端为半胱氨酸，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。
6. 根据权利要求 5所述的应用， 其特征在于： 所述二肽的 C端氨基酸选自碱性氨基酸或脂 肪族类氨基酸。
7. 根据权利要求 6所述的应用， 其特征在于： 所述碱性氨基酸选自 H、 K。
8. 根据权利要求 6所述的应用， 其特征在于： 所述脂肪族类氨基酸选自 Α、 I。
PCT/CN2014/084089 2014-08-11 2014-08-11 二肽作为ace酶活性抑制剂的应用 Ceased WO2016023150A1 (zh)

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CN201480081162.0A CN106573035B (zh) 2014-08-11 2014-08-11 二肽作为ace酶活性抑制剂的应用
US15/503,328 US10441624B2 (en) 2014-08-11 2014-08-11 Application of dipeptide as ace enzyme activity inhibitor
EP14899664.8A EP3219324B1 (en) 2014-08-11 2014-08-11 Application of dipeptide as ace enzyme activity inhibitor
PCT/CN2014/084089 WO2016023150A1 (zh) 2014-08-11 2014-08-11 二肽作为ace酶活性抑制剂的应用

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