高等学校化学学报 ›› 2016, Vol. 37 ›› Issue (7): 1287-1292.doi: 10.7503/cjcu20160295

• 有机化学 • 上一篇    下一篇

基于α螺旋肽与多酚缀合的HIV-1融合抑制剂的设计、 合成及活性初筛

程思绮1, 梁国栋2, 姜喜凤2, 王潮2(), 刘克良1,2()   

  1. 1. 沈阳药科大学制药工程学院, 沈阳 110016
    2. 军事医学科学院毒物药物研究所, 北京 100850
  • 收稿日期:2016-04-29 出版日期:2016-07-10 发布日期:2016-06-22
  • 基金资助:
    国家自然科学基金(批准号: 81573266, 81373266)资助

Design, Sythesis and Biological Evaluation of Polyphenol-α-helical Peptide Conjugates as Potent HIV-1 Fusion Inhibitors

CHENG Siqi1, LIANG Guodong2, JIANG Xifeng2, WANG Chao2,*(), LIU Keliang1,2,*()   

  1. 1. School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
    2. Beijing Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China
  • Received:2016-04-29 Online:2016-07-10 Published:2016-06-22
  • Contact: WANG Chao,LIU Keliang E-mail:chaow301@gmail.com;keliangliu55@126.com
  • Supported by:
    † Supported by the National Natural Science Foundation of China(Nos.81573266, 81373266)

摘要:

α螺旋多肽与羟基酪醇等多酚类化合物通过共价键缀合, 期望二者在发挥各自生物学作用的同时产生协同效应, 据此设计了HIV-1融合抑制多肽. 圆二色光谱表征结果表明, 所设计的缀合多肽呈典型的α螺旋结构特征, 且可以与靶标N36相互作用. HIV-1包膜糖蛋白(Env)介导的细胞-细胞融合活性测试结果表明, 这些具有α螺旋结构的缀合多肽可以在低微摩尔水平抑制病毒融合.

关键词: 人免疫缺陷病毒Ⅰ型, 融合抑制剂, α琢螺旋肽, 多酚

Abstract:

De novo-designed peptide sequences with an α-helical conformation can prevent fusogenic gp41 six-helical bundle(6HB) formation by specifically interacting with the Human Immunodificiency virus type 1(HIV-1) gp41 N-terminal heptad repeat(NHR) region, thus inhibiting HIV-1-cell membrane fusion. Meanwhile, polyphenols, such as hydroxytyrosol(HT) and (-)-epigallocatechin gallate(EGCG), are a major group of natural compounds with a broad spectrum of antiviral activity. In this paper, mHT were designed and obtained based on 3,4-dihydroxymethylacetic acid. Then, mHT and other bioactive polyphenols, were covalently conjugated to a certain α-helical peptide through specific linkers with different lengths and flexibilities. These conjugates interacted with the gp41 NHR region and exhibited promising fusion inhibitory activity, with IC50 values in the low micromolar range. This study provides a promising strategy for the development of fusion inhibitors against viruses with class I fusion proteins.

Key words: Human immunodificiency virus type 1(HIV-1), Fusion inhibitor, α-Helical peptide, Polyphenol

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