高等学校化学学报 ›› 2013, Vol. 34 ›› Issue (9): 2102-2107.doi: 10.7503/cjcu20130391

• 有机化学 • 上一篇    下一篇

二价HIV-1融合抑制剂的设计、合成与活性评价

凌彦博, 王昆, 姜喜凤, 蔡利锋, 刘克良   

  1. 军事医学科学院毒物药物研究所, 北京 100850
  • 收稿日期:2013-04-28 出版日期:2013-09-10 发布日期:2013-08-30
  • 作者简介: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:keliangliu@yahoo.com
  • 基金资助:

    国家自然科学基金(批准号:81072581,81273434);国家重大新药创制科技重大专项(批准号:2012ZX09301003)资助.

Design, Synthesis and Activity Evaluation of Novel Bivalent HIV-1 Fusion Inhibitor

LING Yan-Bo, WANG Kun, JIANG Xi-Feng, CAI Li-Feng, LIU Ke-Liang   

  1. Institute of Pharmacology and Toxicology, Academy of Military Medical Science, Beijing 100850, China
  • Received:2013-04-28 Online:2013-09-10 Published:2013-08-30

摘要:

针对人免疫缺陷病毒跨膜糖蛋白(HIV-1 gp41)N末端重复序列靶标设计二价融合抑制剂, 以C肽为模板, 通过共价交联形成类似发夹结构的相互平行的2条肽链, 研究了二价C肽分子不同连接位点与不同连接臂对抗HIV融合活性的影响. 细胞-细胞融合活性测试表明, 与单价分子相比, 所设计的基于N末端交联的C34或T20的二价分子在前体共价交联后, 活性明显提升. 基于C34或T20的N末端与C末端均存在发生协同效应的可能性, 在C34的N末端设计中β-丙氨酸为最适连接臂, 而在C末端的设计中C34C的融合活性提高最大. 单价分子CβAC34经过氧化形成二硫键连接的二价分子BiCβAC34, 融合活性从43.7 nmol/L提高到6.4 nmol/L, 表明二价抑制剂中2条C肽链间具有良好的协同效应. 本文结果表明, 针对gp41靶标设计的二价融合抑制剂能够相互协同.

关键词: 跨膜糖蛋白gp41, 人免疫缺陷病毒(HIV), 二价分子, 融合抑制剂, 多肽

Abstract:

Multivalent inhibitor is an efficient strategy for inhibitor design based on an additive effect of ΔG. In this work, we chose C34 and T20 as the template sequences to study bivalent inhibitors targeting HIV-1 gp41 NHR domain. We optimized the crosslink sites and linkers to improve anti-HIV activities of the bivalent fusion inhibitors. Compared to monovalent molecules, significant cooperative effects in the anti-cell-cell fusion activity were observed in the bivalent inhibitors, at either N- or C-terminal crosslink of both C34 and T20. β-Alanine may be the most suitable linker for N-terminal crosslink, while C34C is the best C-terminal crosslinked molecule. Specially, the anti-HIV IC50 value of peptide BiCβAC34 was improved from 43.7 nmol/L to 6.4 nmol/L, indicating the two C-peptide chains had a cooperative effect. The results show that bivalent fusion inhibitor for gp41 design could appear a cooperative effect.

Key words: Transmembrane glycoprotein gp41, Human immunodeficiency virus(HIV), Bivalent molecule, Fusion inhibitor, Peptide

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