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学科主题: 生命有机化学
题名: Design of wide-spectrum inhibitors targeting coronavirus main proteases
其他题名: 作用于冠状病毒主要蛋白酶的广谱抑制剂的设计
作者: Yang HT(杨海涛) ; Xie WQ(谢卫青) ; Xue Xiaoyu ; Yang Kailin ; Ma Jing ; Liang Wenxue ; Zhao Qi ; Zou Zhe ; Pei DQ(裴端卿) ; John Ziebuhr ; Rolf Hilgenfeld ; Kwok Yung Yuen ; Luet Wong ; Guangxia Gao ; Saijuan Chen ; Zhu Chen ; Ma DW(马大为) ; Mark Bartlam ; Zihe Rao
通讯作者: 马大为 ; Zihe Rao
刊名: PLoS. Biol.
发表日期: 2005
卷: 3, 期:10, 页:1742-1752
收录类别: SCI
部门归属: 中国科学院上海有机化学所; 复旦大学
英文摘要: The genus Coronavirus contains about 25 species of coronaviruses (CoVs), which are important pathogens causing highly prevalent diseases and often severe or fatal in humans and animals. No licensed specific drugs are available to prevent their infection. Different host receptors for cellular entry, poorly conserved structural proteins ( antigens), and the high mutation and recombination rates of CoVs pose a significant problem in the development of wide-spectrum anti-CoV drugs and vaccines. CoV main proteases (M-pro s), which are key enzymes in viral gene expression and replication, were revealed to share a highly conservative substrate-recognition pocket by comparison of four crystal structures and a homology model representing all three genetic clusters of the genus Coronavirus. This conclusion was further supported by enzyme activity assays. Mechanism-based irreversible inhibitors were designed, based on this conserved structural region, and a uniform inhibition mechanism was elucidated from the structures of M pro-inhibitor complexes from severe acute respiratory syndrome-CoV and porcine transmissible gastroenteritis virus. A structure-assisted optimization program has yielded compounds with fast in vitro inactivation of multiple CoV M pro s, potent antiviral activity, and extremely low cellular toxicity in cell-based assays. Further modification could rapidly lead to the discovery of a single agent with clinical potential against existing and possible future emerging CoV-related diseases.
语种: 英语
相关网址: 查看原文
WOS记录号: WOS:000232404600009
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内容类型: 期刊论文
URI标识: http://ir.sioc.ac.cn/handle/331003/15479
Appears in Collections:生命有机化学国家重点实验室_期刊论文

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Recommended Citation:
Yang HT,Xie WQ,Xue Xiaoyu,et al. Design of wide-spectrum inhibitors targeting coronavirus main proteases[J]. PLoS. Biol.,2005,3(10):1742-1752.
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