Design of wide-spectrum inhibitors targeting coronavirus main proteases

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	Design of wide-spectrum inhibitors targeting coronavirus main proteases
	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
刊名	PLoS. Biol.
	2005
卷号	3 期号:10 页码:1742-1752
ISSN号	1544-9173
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
通讯作者	马大为 ; Zihe Rao
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.
学科主题	生命有机化学
收录类别	SCI
原文出处	http://dx.doi.org/10.1371/journal.pbio.0030324
语种	英语
WOS记录号	WOS:000232404600009
公开日期	2013-02-19
内容类型	期刊论文
源URL	[http://202.127.28.38/handle/331003/15479]
专题	上海有机化学研究所_生命有机化学国家重点实验室
推荐引用方式 GB/T 7714	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.
APA	杨海涛.,谢卫青.,Xue Xiaoyu.,Yang Kailin.,Ma Jing.,...&Zihe Rao.(2005).Design of wide-spectrum inhibitors targeting coronavirus main proteases.PLoS. Biol.,3(10),1742-1752.
MLA	杨海涛,et al."Design of wide-spectrum inhibitors targeting coronavirus main proteases".PLoS. Biol. 3.10(2005):1742-1752.