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

Guo, J; Douangamath, A; Song, W; Coker, AR; Chan, AWE; Wood, SP; Cooper, JB; ... Von Delft, F; + view all (2020) In crystallo-screening for discovery of human norovirus 3C-like protease inhibitors. Journal of Structural Biology: X , Article 100031. 10.1016/j.yjsbx.2020.100031. Green open access

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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.

Type: Article
Title: In crystallo-screening for discovery of human norovirus 3C-like protease inhibitors
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.yjsbx.2020.100031
Publisher version: https://doi.org/10.1016/j.yjsbx.2020.100031
Language: English
Additional information: Copyright © 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).
Keywords: X-ray crystallography, Structural biology, Fragment screening, Drug discovery, 3C-like protease, Anti-virals
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Department of Education
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research
URI: https://discovery.ucl.ac.uk/id/eprint/10106094
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