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化学学报
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化学学报 ›› 2007, Vol. 65 ›› Issue (16): 1707-1712. 上一篇    下一篇

研究论文

非肽类SARS冠状病毒3CL蛋白酶抑制剂的设计与活性表征

刘莹*,1, 郑腾飞1, 金凤1, 周璐1, 刘振明1,2, 魏平1,2, 来鲁华*,1,2   

  1. (1北京大学化学与分子工程学院北京分子科学国家实验室(筹)分子动态与稳态结构国家重点实验室 北京 100871)
    (2北京大学理论生物学中心 北京 100871)
  • 投稿日期:2007-03-30 修回日期:2007-06-22 发布日期:2007-08-28
  • 通讯作者: 刘莹, 来鲁华

Design and Bioassay of Non-peptidic Inhibitors of SARS Coronavirus 3C-like Proteinase

LIU Ying*,1; ZHENG Teng-Fei1; JIN Feng1; ZHOU Lu1; LIU Zhen-Ming1,2; WEI Ping1,2; LAI Lu-Hua*,1,2   

  1. (1 Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871)
    (2 Center for Theoretical Biology, Peking University, Beijing 100871)
  • Received:2007-03-30 Revised:2007-06-22 Published:2007-08-28
  • Contact: LIU Ying; LAI Lu-Hua

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SARS冠状病毒3CL蛋白酶是SARS病毒复制过程中的主要蛋白酶, 针对其开展药物设计有望得到有效的抗SARS病毒药物. 本文基于SARS冠状病毒3CL蛋白酶的三维结构, 对现有化学试剂及临床用药数据库进行虚拟筛选, 选出可能对SARS冠状病毒3CL蛋白酶有抑制的非肽化合物进行初步活性测试, 并研究了已知的人鼻病毒3C蛋白酶抑制剂对SARS冠状病毒3CL蛋白酶的活性, 合成了两种母环的衍生物, 得到靛红和哌嗪两类SARS冠状病毒3CL蛋白酶的抑制剂, 其中一个靛红类化合物的IC50为0.76 µmol•L－1; 而抗组胺药哌嗪类化合物对SARS冠状病毒3CL蛋白酶及细胞培育的SARS病毒的抑制作用, 提示了老药可以开发出新的用途.

关键词: SARS冠状病毒3CL蛋白酶, 虚拟筛选, 非肽抑制剂, 活性测试

Severe acute respiratory syndrome (SARS) coronavirus 3C-like proteinase is the key enzyme for the maturation of the virus and has been proposed to be a key target for structure based drug design against SARS. In this paper, based on the three-dimensional structure of SARS coronavirus 3C-like proteinase, the available chemical database (ACD) and clinical drug databases were used for virtual screening, and the candidate non-peptidic compounds were purchased or synthesized. Several human rhinovirus (HRV) 3C protease inhibitors were also synthesized. All the compounds were tested against SARS 3C-like proteinase bioassay. Two types of compounds including hydroxyzine dihydrochloride, a well known antihistamine, were found to inhibit the enzyme and SARS virus in cell cultivating; one of the isatin compounds shows significant inhibition with an IC50 of (0.76±0.02) µmol•L－1. The primary result suggested that drugs in clinical usage can be developed for new purpose.

Key words: SARS coronavirus 3C-like proteinase, virtual screen, non-peptidic inhibitor, bioassay