Enterovirus 71 and Coxsackievirus A16 3C Proteases: Binding to Rupintrivir and Their Substrates and Anti-Hand, Foot, and Mouth Disease Virus Drug Design

doi:10.1128/JVI.00787-11

	Enterovirus 71 and Coxsackievirus A16 3C Proteases: Binding to Rupintrivir and Their Substrates and Anti-Hand, Foot, and Mouth Disease Virus Drug Design
	Lu, Guangwen 2,3; Qi, Jianxun 2; Chen, Zhujun 2; Xu, Xiang 2; Gao, Feng 4,5; Lin, Daizong 7; Qian, Wangke 7; Liu, Hong7 ; Jiang, Hualiang7 ; Yan, Jinghua 2
刊名	JOURNAL OF VIROLOGY
	2011-10
卷号	85 期号:19 页码:10319-10331
ISSN号	0022-538X
DOI	10.1128/JVI.00787-11
文献子类	Article
英文摘要	Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the major causative agents of hand, foot, and mouth disease (HFMD), which is prevalent in Asia. Thus far, there are no prophylactic or therapeutic measures against HFMD. The 3C proteases from EV71 and CVA16 play important roles in viral replication and are therefore ideal drug targets. By using biochemical, mutational, and structural approaches, we broadly characterized both proteases. A series of high-resolution structures of the free or substrate-bound enzymes were solved. These structures, together with our cleavage specificity assay, well explain the marked substrate preferences of both proteases for particular P4, P1, and P1' residue types, as well as the relative malleability of the P2 amino acid. More importantly, the complex structures of EV71 and CVA16 3Cs with rupintrivir, a specific human rhinovirus (HRV) 3C protease inhibitor, were solved. These structures reveal a half-closed S2 subsite and a size-reduced S1' subsite that limit the access of the P1' group of rupintrivir to both enzymes, explaining the reported low inhibition activity of the compound toward EV71 and CVA16. In conclusion, the detailed characterization of both proteases in this study could direct us to a proposal for rational design of EV71/CVA16 3C inhibitors.
资助项目	Innovative Research Group of the National Natural Science Foundation of China (NSFC)[81021003]
WOS关键词	ANTIVIRAL ACTIVITY ; EPIDEMIOLOGIC FEATURES ; MOLECULAR EPIDEMIOLOGY ; STRUCTURAL BASIS ; INFECTION ; INHIBITORS ; OUTBREAK ; TAIWAN ; SYSTEM ; SPECIFICITY
WOS研究方向	Virology
语种	英语
出版者	AMER SOC MICROBIOLOGY
WOS记录号	WOS:000296253900064
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278381]
专题	药物化学研究室药物发现与设计中心
通讯作者	Gao, George F.
作者单位	1.Chinese Acad Sci, Beijing Inst Life Sci, Beijing 100101, Peoples R China; 2.Chinese Acad Sci, Chinese Acad Sci Key Lab Pathogen Microbiol & Imm, Inst Microbiol, Beijing 100101, Peoples R China 3.Chinese Acad Sci, Grad Univ, Beijing 100049, Peoples R China; 4.Sichuan Univ, Sch Life Sci, Chengdu 610064, Sichuan, Peoples R China; 5.Chinese Acad Sci, Natl Lab Macromol, Inst Biophys, Beijing 100101, Peoples R China; 6.Chinese Acad Sci, China Japan Joint Lab Mol Immunol & Mol Microbio, Inst Microbiol, Beijing 100101, Peoples R China; 7.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Lu, Guangwen,Qi, Jianxun,Chen, Zhujun,et al. Enterovirus 71 and Coxsackievirus A16 3C Proteases: Binding to Rupintrivir and Their Substrates and Anti-Hand, Foot, and Mouth Disease Virus Drug Design[J]. JOURNAL OF VIROLOGY,2011,85(19):10319-10331.
APA	Lu, Guangwen.,Qi, Jianxun.,Chen, Zhujun.,Xu, Xiang.,Gao, Feng.,...&Gao, George F..(2011).Enterovirus 71 and Coxsackievirus A16 3C Proteases: Binding to Rupintrivir and Their Substrates and Anti-Hand, Foot, and Mouth Disease Virus Drug Design.JOURNAL OF VIROLOGY,85(19),10319-10331.
MLA	Lu, Guangwen,et al."Enterovirus 71 and Coxsackievirus A16 3C Proteases: Binding to Rupintrivir and Their Substrates and Anti-Hand, Foot, and Mouth Disease Virus Drug Design".JOURNAL OF VIROLOGY 85.19(2011):10319-10331.