高等学校化学学报 ›› 2016, Vol. 37 ›› Issue (5): 881-885.doi: 10.7503/cjcu20160125

• 有机化学 • 上一篇    下一篇

异肽键交联的N肽类HIV-1融合抑制剂的设计、 合成及活性评价

李雪, 来文庆, 姜喜凤, 王潮(), 刘克良()   

  1. 军事医学科学院毒物药物研究所, 抗毒药物与毒理学国家重点实验室, 北京 100850
  • 收稿日期:2016-03-02 出版日期:2016-05-10 发布日期:2016-04-15
  • 作者简介:联系人简介: 刘克良, 男, 博士, 研究员, 博士生导师, 主要从事多肽药物、 核酸化学及药用高分子材料的研究. E-mail:keliangliu55@126.com
    王潮, 男, 博士, 助理研究员, 主要从事多肽药物的研究. E-mail: chaow301@gmail.com
  • 基金资助:
    国家自然科学基金(批准号: 81373266, 81573266)资助

Design, Synthesis and Activity Screening of Isopeptide Bond-tethered N Peptides as HIV-1 Fusion Inhibitors

LI Xue, LAI Wenqing, JIANG Xifeng, WANG Chao*(), LIU Keliang*()   

  1. Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China
  • Received:2016-03-02 Online:2016-05-10 Published:2016-04-15
  • 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.81373266, 81573266)

摘要:

报道了一种通过在HIV-1 gp41 NHR区域的多肽(N肽)之间引入异肽键稳定N3螺旋的新方法; 以天然N肽序列N38为模板, 采用此方法设计合成了一系列异肽键交联的N38三股α螺旋结构. 该结构具有极强的热稳定性和纳摩尔水平抑制HIV-1包膜糖蛋白(Env)介导的细胞融合活性.

关键词: 人免疫缺陷病毒Ⅰ型, 融合抑制剂, N端重复序列, 卷曲螺旋

Abstract:

Peptides derived from the N-terminal heptad repeat(N-peptides) of HIV-1 gp41 can exhibit highly potent anti-HIV-1 activity when presented in a trimeric coiled-coil conformation. In this paper, the NHR trimeric coiled coils were designed based on a naturally occurring N-peptide, e.g. N38, on which engineered acyl transfer active sites were incorporated at the e/g-positions of heptad repeats to generate isopeptide bond cross-links. These isopeptide bond-tethered N-peptides exhibited exceptional thermal stability and possessed promising inhibitory activity on HIV-1 env-mediated cell-cell fusion.

Key words: HIV-1, Fusion inhibitor, N-terminal heptad repeat, Coiled coil

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