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

DOI: 10.1016/j.yjsbx.2020.100031 DOI Help

Authors: Jingxu Guo (University College London) , Alice Douangamath (Diamond Light Source) , Weixiao Song (University College London) , Alun Coker (University College London) , A. W. Edith Chan (University College London) , Steve P. Wood (University College London) , Jonathan B. Cooper (University College London; Birkbeck, University of London) , Efrat Resnick (Weizmann Institute of Science) , Nir London (Weizmann Institute of Science) , Frank Von Delft (Diamond Light Source)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Structural Biology: X

State: Published (Approved)
Published: July 2020

Open Access Open Access

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 10 were located in the symmetric central cavity of the tetramer.

Diamond Keywords: Gastroenteritis; Viruses; Enzymes

Subject Areas: Biology and Bio-materials, Medicine, Chemistry

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 22/07/2020 08:36


Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Catalysis Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)