In crystallo-screening for discovery of human norovirus 3C-like protease inhibitors

IF 3.5 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jingxu Guo , Alice Douangamath , Weixiao Song , Alun R. Coker , A.W. Edith Chan , Steve P. Wood , Jonathan B. Cooper , Efrat Resnick , Nir London , Frank von Delft
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引用次数: 2

Abstract

Outbreaks of human epidemic nonbacterial gastroenteritis are mainly caused by noroviruses. Viral replication requires a 3C-like cysteine protease (3CLpro) which processes the 200 kDa viral polyprotein into six functional proteins. The 3CLpro has attracted much interest due to its potential as a target for antiviral drugs. A system for growing high-quality crystals of native Southampton norovirus 3CLpro (SV3CP) has been established, allowing the ligand-free crystal structure to be determined to 1.3 Å in a tetrameric state. This also allowed crystal-based fragment screening to be performed with various compound libraries, ultimately to guide drug discovery for SV3CP. A total of 19 fragments were found to bind to the protease out of the 844 which were screened. Two of the hits were located at the active site of SV3CP and showed good inhibitory activity in kinetic assays. Another 5 were found at the enzyme’s putative RNA-binding site and a further 11 were located in the symmetric central cavity of the tetramer.

Abstract Image

人诺如病毒3C样蛋白酶抑制剂的晶体内筛选
人类流行性非细菌性肠胃炎的暴发主要由诺如病毒引起。病毒复制需要3C样半胱氨酸蛋白酶(3CLpro),该蛋白酶将200kDa的病毒多蛋白加工成六种功能蛋白。3CLpro由于其作为抗病毒药物靶点的潜力而引起了人们的极大兴趣。已经建立了一个生长天然南安普敦诺如病毒3CLpro(SV3CP)高质量晶体的系统,使无配体的晶体结构在四聚体状态下被确定为1.3Å。这也允许用各种化合物文库进行基于晶体的片段筛选,最终指导SV3CP的药物发现。在筛选的844个片段中,共发现19个片段与蛋白酶结合。其中两个命中物位于SV3CP的活性位点,并且在动力学测定中显示出良好的抑制活性。另外5个位于酶推定的RNA结合位点,另外11个位于四聚体的对称中心腔中。
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来源期刊
Journal of Structural Biology: X
Journal of Structural Biology: X Biochemistry, Genetics and Molecular Biology-Structural Biology
CiteScore
6.50
自引率
0.00%
发文量
20
审稿时长
62 days
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