高等学校化学学报 ›› 2014, Vol. 35 ›› Issue (10): 2100-2104.doi: 10.7503/cjcu20140495

• 有机化学 • 上一篇    下一篇

以gp41为靶标的小分子-多肽缀合物作为HIV-1融合抑制剂的设计、合成及活性初筛

梁国栋1, 王潮2, 史卫国2, 王昆2, 姜喜凤2, 许笑宇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:2014-05-28 出版日期:2014-10-10 发布日期:2014-09-11
  • 作者简介:联系人简介: 刘克良, 男, 博士, 研究员, 博士生导师, 主要从事多肽药物和核酸化学研究. E-mail: keliangliu55@126.com
  • 基金资助:
    国家自然科学基金(批准号: 81373266)和“重大新药创制”科技重大专项项目(批准号: 2012ZX09301003)资助

Design, Synthesis and Activity Prescreening of Small Molecule-Peptide Conjugates as HIV-1 Fusion Inhibitors Targeting gp41

LIANG Guodong1, WANG Chao2, SHI Weiguo2, WANG Kun2, JIANG Xifeng2, XU Xiaoyu2, 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:2014-05-28 Online:2014-10-10 Published:2014-09-11
  • Contact: LIU Keliang E-mail:keliangliu55@126.com
  • Supported by:
    Supported by the National Natural Science Foundation of China(No.81373266) and the “Creation of Major New Drugs” Science and Technology Major Projects of China(No.2012ZX09301003)

摘要:

芳基吡咯类小分子化合物NB-2衍生物(Noc或Npc)与衍生于C34中的靶标特异性多肽P26所形成的缀合物具有低纳摩尔水平的融合抑制活性. 本文通过不同长度或不同柔性的连接臂将Noc或Npc与衍生于C34的靶标特异性多肽P27缀合, 探讨了C34中a位残基I635和连接臂对缀合物活性的影响. 人体免疫缺陷病毒1型(HIV-1)Env介导的细胞-细胞融合实验结果表明, 多肽与小分子之间产生了强的协同作用.

关键词: 人体免疫缺陷病毒1型(HIV-1), 融合抑制剂, 缀合物

Abstract:

HIV-1 fusion inhibitors target the transmembrane subunit(gp41) of HIV-1 envelopeglycoproteins. Previous studies had shown that the small molecule pyrrole derivatives, Noc or Npc, can act as a substitute for the pocket binding domain of the C34 peptide, and the small molecule-peptide conjugates exhibit low nanomolar IC50 value in the cell-cell fusion assay. In this paper, pocket-specific small molecule and P27 peptide were covalently linked together through specified linkers with different lengths and flexibilities. Small molecule-peptide conjugates exhibited significant inhibitory activity on HIV-1 Env-mediated cell-cell fusion assay.

Key words: HIV-1, Fusion inhibitor, Conjugate

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