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

doi:10.7503/cjcu20160295

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

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. 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 Chao^2,^*(), LIU Keliang^1,^2,^*()

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/Abstract

摘要：

将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

中图分类号:

O629.72

TrendMD:

程思绮, 梁国栋, 姜喜凤, 王潮, 刘克良. 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. 高等学校化学学报, 2016, 37(7): 1287.

CHENG Siqi, LIANG Guodong, JIANG Xifeng, WANG Chao, LIU Keliang. Design, Sythesis and Biological Evaluation of Polyphenol-α-helical Peptide Conjugates as Potent HIV-1 Fusion Inhibitors^†. Chem. J. Chinese Universities, 2016, 37(7): 1287.

图/表 5

Fig.1 Ineraction between NHR and CHR of HIV gp41(A) Association of the CHR to NHR to form 6-HB; (B) CHR and NHR interact in antiparallel orientation to form 6HB.

Scheme 1 Synthesis routes of compound 5

Fig.2 Structures of polyphenols and designed conjugates(A) Chemical formula of mHT, PA and GA; (B) sequence of designed conjugates.

Fig.3 CD spectra of mHT-βAla-m4HR and its complex with gp41 NHR peptidesa. mHT-βAla-m4HR; b. N36; c. mHT-βAla-m4HR+N36; d. mHT-βAla-m4HR/N36.

Table 1 Inhibitory activities of conjugates on HIV-1 Env-mediated cell-cell fusiona

Compd.	Structure	I $C 50 b$ /(μmol·L^-1)
m4HR	Ac-IEELIKK SEELIKK IEEQIKK QEESIKK	36.910±2.047
mHT-βAla-m4HR	mHT-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK	11.247±1.490
mHT-Aca-m4HR	mHT-Aca-IEELIKK SEELIKK IEEQIKK QEESIKK	5.346±0.8233
mHT-PEG₃-m4HR	mHT-PEG₃-IEELIKK SEELIKK IEEQIKK QEESIKK	7.036±1.0327
PA-βAla-m4HR	PA-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK	11.538±1.568
GA-βAla-m4HR	GA-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK	23.373±2.495

Table 1 Inhibitory activities of conjugates on HIV-1 Env-mediated cell-cell fusiona

Compd.	Structure	I $C 50 b$ /(μmol·L^-1)
m4HR	Ac-IEELIKK SEELIKK IEEQIKK QEESIKK	36.910±2.047
mHT-βAla-m4HR	mHT-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK	11.247±1.490
mHT-Aca-m4HR	mHT-Aca-IEELIKK SEELIKK IEEQIKK QEESIKK	5.346±0.8233
mHT-PEG₃-m4HR	mHT-PEG₃-IEELIKK SEELIKK IEEQIKK QEESIKK	7.036±1.0327
PA-βAla-m4HR	PA-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK	11.538±1.568
GA-βAla-m4HR	GA-βAla-IEELIKK SEELIKK IEEQIKK QEESIKK	23.373±2.495

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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

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

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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

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

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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

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