Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

DOI: 10.1038/s41467-020-18709-w

Authors: Alice Douangamath (Diamond Light Source; Research Complex at Harwell) , Daren Fearon (Diamond Light Source) , Paul Gehrtz (Weizmann Institute of Science) , Tobias Krojer (Structural Genomics Consortium, University of Oxford) , Petra Lukacik (Diamond Light Source; Research Complex at Harwell) , C. David Owen (Diamond Light Source; Research Complex at Harwell) , Efrat Resnick (Weizmann Institute of Science) , Claire Strain-Damerell (Diamond Light Source; Research Complex at Harwell) , Anthony Aimon (Diamond Light Source; Research Complex at Harwell) , Péter Ábrányi-Balogh (Research Centre for Natural Sciences (RCNS-HAS)) , Jose Brandao-Neto (Diamond Light Source; Research Complex at Harwell) , Anna Carbery (Diamond Light Source; University of Oxford) , Gemma Davison (Newcastle University) , Alexandre Dias (Diamond Light Source) , Thomas D. Downes (University of York) , Louise Dunnett (Diamond Light Source) , Michael Fairhead (Structural Genomics Consortium, University of Oxford) , James D. Firth (University of York) , S. Paul Jones (University of York) , Aaron Keeley (Research Centre for Natural Sciences (RCNS-HAS)) , György M. Keserü (Research Centre for Natural Sciences (RCNS-HAS)) , Hanna F. Klein (University of York) , Mathew P. Martin (Newcastle University) , Martin M. Noble (Newcastle University) , Peter O’brien (University of York) , Ailsa Powell (Diamond Light Source) , Rambabu N. Reddi (Weizmann Institute of Science) , Rachael Skyner (Diamond Light Source; Research Complex at Harwell) , Matthew Snee (Diamond Light Source) , Michael J. Waring (Newcastle University) , Conor Wild (Diamond Light Source) , Nir London (Weizmann Institute of Science) , Frank Von Delft (Diamond Light Source) , Martin A. Walsh (Diamond Light Source)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 11

State: Published (Approved)
Published: October 2020

Abstract: COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.

Journal Keywords: Enzymes; Mass spectrometry; Proteases; X-ray crystallography

Diamond Keywords: COVID-19; Viruses

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

Diamond Offline Facilities: XChem
Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 09/10/2020 13:15

Documents:
s41467-020-18709-w.pdf

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening