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

Alice Douangamath, Daren Fearon, Paul Gehrtz, Tobias Krojer, Petra Lukacik, C. David Owen, Efrat Resnick, Claire Strain-Damerell, Anthony Aimon, Péter Ábrányi-Balogh, José Brandão-Neto, Anna Carbery, Gemma Davison, Alexandre Dias, Thomas D. Downes, Louise Dunnett, Michael Fairhead, James D. Firth, S. Paul Jones, Aaron Keeley, György M. Keserü, Hanna F. Klein, Mathew P. Martin, Martin E. M. Noble, Peter O’Brien, Ailsa Powell, Rambabu N. Reddi, Rachael Skyner, Matthew Snee, Michael J. Waring, Conor Wild, Nir London (), Frank Delft () and Martin A. Walsh ()
Additional contact information
Alice Douangamath: Diamond Light Source Ltd., Harwell Science and Innovation Campus
Daren Fearon: Diamond Light Source Ltd., Harwell Science and Innovation Campus
Paul Gehrtz: Weizmann Institute of Science
Tobias Krojer: Structural Genomics Consortium, University of Oxford
Petra Lukacik: Diamond Light Source Ltd., Harwell Science and Innovation Campus
C. David Owen: Diamond Light Source Ltd., Harwell Science and Innovation Campus
Efrat Resnick: Weizmann Institute of Science
Claire Strain-Damerell: Diamond Light Source Ltd., Harwell Science and Innovation Campus
Anthony Aimon: Diamond Light Source Ltd., Harwell Science and Innovation Campus
Péter Ábrányi-Balogh: Medicinal Chemistry Research Group, Research Centre for Natural Sciences
José Brandão-Neto: Diamond Light Source Ltd., Harwell Science and Innovation Campus
Anna Carbery: Diamond Light Source Ltd., Harwell Science and Innovation Campus
Gemma Davison: Cancer Research UK Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Bedson Building, Newcastle University
Alexandre Dias: Diamond Light Source Ltd., Harwell Science and Innovation Campus
Thomas D. Downes: University of York
Louise Dunnett: Diamond Light Source Ltd., Harwell Science and Innovation Campus
Michael Fairhead: Structural Genomics Consortium, University of Oxford
James D. Firth: University of York
S. Paul Jones: University of York
Aaron Keeley: Medicinal Chemistry Research Group, Research Centre for Natural Sciences
György M. Keserü: Medicinal Chemistry Research Group, Research Centre for Natural Sciences
Hanna F. Klein: University of York
Mathew P. Martin: Cancer Research UK Drug Discovery Unit, Newcastle University Centre for Cancer, Paul O’Gorman Building, Medical School, Framlington Place, Newcastle University
Martin E. M. Noble: Cancer Research UK Drug Discovery Unit, Newcastle University Centre for Cancer, Paul O’Gorman Building, Medical School, Framlington Place, Newcastle University
Peter O’Brien: University of York
Ailsa Powell: Diamond Light Source Ltd., Harwell Science and Innovation Campus
Rambabu N. Reddi: Weizmann Institute of Science
Rachael Skyner: Diamond Light Source Ltd., Harwell Science and Innovation Campus
Matthew Snee: Diamond Light Source Ltd., Harwell Science and Innovation Campus
Michael J. Waring: Cancer Research UK Drug Discovery Unit, Newcastle University Centre for Cancer, Chemistry, School of Natural and Environmental Sciences, Bedson Building, Newcastle University
Conor Wild: Diamond Light Source Ltd., Harwell Science and Innovation Campus
Nir London: Weizmann Institute of Science
Frank Delft: Diamond Light Source Ltd., Harwell Science and Innovation Campus
Martin A. Walsh: Diamond Light Source Ltd., Harwell Science and Innovation Campus

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18709-w

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