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有机化学
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有机化学 ›› 2009, Vol. 29 ›› Issue (04): 536-547. 上一篇    下一篇

综述与进展

靶向整合过程不同步骤的HIV-1整合酶抑制剂的结构类型和研究进展

曾立凡 ; 龙亚秋*   

  1. (中国科学院上海药物研究所新药研究国家重点实验室 上海 201203)
  • 收稿日期:2008-05-28 修回日期:2008-09-22 发布日期:2009-04-20
  • 通讯作者: 龙亚秋

Advances in HIV-1 Integrase Inhibitors Directed toward Different Steps of Integration

Zeng, Lifan ; Long, Yaqiu*
  

  1. (State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
    Chinese Academy of Sciences, Shanghai 201203)
  • Received:2008-05-28 Revised:2008-09-22 Published:2009-04-20
  • Contact: Long, Yaqiu

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被引次数

6

HIV-1整合酶是病毒复制所必需的三个基本酶之一, 为病毒所特有, 人体无对应的酶, 因此整合酶是理想的抗HIV药物设计的新靶标. HIV-1整合酶催化病毒DNA插入宿主染色体的过程涉及到整合酶与前病毒DNA形成整合前复合物、病毒DNA的3’末端切断和DNA链转移等步骤, 目前研究得最多的HIV-1整合酶抑制剂是抑制链转移反应的芳基二酮酸化合物, 其中的电子等排体衍生物Raltegravir (MK-0518)于2007年10月被美国食品药品管理局(FDA)批准上市, 而GS-9137处于三期临床试验, 此外还有多个处于临床前研究和临床阶段的药物. 根据抑制剂的不同作用机理, 本综述介绍了近年来所报道的HIV-1整合酶抑制剂的结构类型、药效团模型、研究进展及化学合成, 将整合酶抑制剂分为链转移反应抑制剂、整合酶-DNA结合抑制剂、整合酶3’端切除反应抑制剂、非专一性整合酶抑制剂以及多肽类抑制剂等几大类. 其中链转移反应抑制剂结构类型最丰富、发展最快. 整合酶抑制剂的出现丰富了高效抗逆转录病毒疗法(HAART), 为多重抗药性艾滋病患者提供了新的有效的治疗方案.

关键词: HIV-1整合酶, GS-9137, 抑制剂, Raltegravir (MK-0518), 抗HIV药物

Based on the mode of action, the present paper reviews the HIV-1 integrase inhibitors reported recently with respect to the structure features, pharmacophore analysis, chemical synthesis and the development status, according to the categories of strand transfer inhibitor, IN-DNA interaction inhibitor, 3’-processing inhibitor, non-specific inhibitor and peptide inhibitor, respectively. The strand transfer inhibitor is the most developed class of HIV-1 integrase inhibitors, among which MK-0518 was the first FDA-approved HIV-1 integrase inhibitor as anti-HIV drug. HIV-1 integrase inhibitor has enriched the highly active antiretroviral therapy (HAART) regimen and provides an efficient treatment for multiple drug-resistant patients.

Key words: HIV-1 integrase, inhibitor, anti-HIV drug, GS-9137, raltegravir (MK-0518)