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 von Delft; Martin A. Walsh

doi:10.1038/s41467-020-18709-w

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

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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, …

Nature Communications, Vol.11(1), 5047

07/Oct/2020

DOI: https://doi.org/10.1038/s41467-020-18709-w

PMID: 33028810

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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.

Details

Title: Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease
Creators: Alice Douangamath (null) - Diamond Light Source
Daren Fearon (null) - Diamond Light Source
Paul Gehrtz (null) - The Weizmann Institute of Science
Tobias Krojer (null) - University of Oxford
Petra Lukacik (null) - Diamond Light Source
C. David Owen (null) - Diamond Light Source
Efrat Resnick (null) - The Weizmann Institute of Science
Claire Strain-Damerell (null) - Diamond Light Source
Anthony Aimon (null) - Diamond Light Source
Péter Ábrányi-Balogh (null) - 41___RESEARCH_CENTRE_FOR_NATURAL_SCIENCES_(BUDAPEST)
José Brandão-Neto (null) - Diamond Light Source
Anna Carbery (null) - Diamond Light Source
Gemma Davison (null) - Newcastle University (United Kingdom, Newcastle upon Tyne)
Alexandre Dias (null) - Diamond Light Source
Thomas D. Downes (null) - University of York (United Kingdom, York)
Louise Dunnett (null) - Diamond Light Source
Michael Fairhead (null) - University of Oxford
James D. Firth (null) - University of York (United Kingdom, York)
S. Paul Jones (null) - University of York (United Kingdom, York)
Aaron Keeley (null) - 41___RESEARCH_CENTRE_FOR_NATURAL_SCIENCES_(BUDAPEST)
György M. Keserü (null) - 41___RESEARCH_CENTRE_FOR_NATURAL_SCIENCES_(BUDAPEST)
Hanna F. Klein (null) - University of York (United Kingdom, York)
Mathew P. Martin (null) - Newcastle University (United Kingdom, Newcastle upon Tyne)
Martin E.M. Noble (null) - Newcastle University (United Kingdom, Newcastle upon Tyne)
Peter O’Brien (null) - University of York (United Kingdom, York)
Ailsa Powell (null) - Diamond Light Source
Rambabu N. Reddi (null) - The Weizmann Institute of Science
Rachael Skyner (null) - Diamond Light Source
Matthew Snee (null) - Diamond Light Source
Michael J. Waring (null) - Newcastle University (United Kingdom, Newcastle upon Tyne)
Conor Wild (null) - Diamond Light Source
Nir London (null) - The Weizmann Institute of Science
Frank von Delft (Corresponding Author) - Diamond Light Source
Martin A. Walsh (null) - Diamond Light Source
Resource Type: Journal article
Publication Details: Nature Communications, Vol.11(1), 5047
Number of pages: 11
Language: English
DOI: https://doi.org/10.1038/s41467-020-18709-w
PMID: 33028810
Grant note: We thank all the staff of Diamond Light Source for providing support and encouragement which allowed us to carry out this work during the COVID-19 lockdown. We also thank the Diamond MX group for their support and expertise, in particular David Aragão, Ralf Flaig, Dave Hall, Katherine McAuley and Mark Williams. We thank Clemens Vonrhein of GlobalPhasing for independent validation of the initially deposited models. We are grateful to AstraZeneca, Astex Pharmaceuticals, Lilly, Pfizer and Vernalis, University of York (T.D.D. and S.P.J.) and the EU (Horizon 2020 program, Marie Skłodowska-Curie grant agreement No. 675899, FRAGNET) (AK and HFK) for support. The SGC is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada, Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Janssen, Merck KGaA Darmstadt Germany, MSD, Novartis Pharma AG, Ontario Ministry of Economic Development and Innovation, Pfizer, São Paulo Research Foundation-FAPESP, Takeda, and Wellcome [106169/ZZ14/ Z]. N.L. is the incumbent of the Alan and Laraine Fischer Career Development Chair. N.L. would like to acknowledge funding from the Israel Science Foundation (grant no. 2462/19), The Israel Cancer Research Fund, the Israeli Ministry of Science Technology (grant no. 3-14763), the Moross Integrated Cancer Center and the Barry Sherman institute for Medicinal Chemistry. This research was supported by Nelson P. Sirotsky. N.L. is also supported by the Helen and Martin Kimmel Center for Molecular Design, Joel and Mady Dukler Fund for Cancer Research, the Estate of Emile Mimran and Virgin JustGiving, and the George Schwartzman Fund. FvD and GMK are grateful for the support of the Foreign Commonwealth and Development Office (UK). ABP received a Postdoctoral Fellowship from the Hungarian Science Foundation (PD124598). Contributions - M.A.W. initiated the project. N.L., F.V.D. and M.A.W. supervised and coordinated the research and analysed data. A.D., D.F., P.G., T.K., P.L., C.S-D., C.D.O., E.F., G.M. M.J.W., N.L., F.V.D. and M.A.W. writing original draft and review, editing of manuscript. A.D., D.F. and A.P. XChem sample preparation, crystallographic data collection, data analysis, P.G. and R.N.R. Chemical synthesis. T.K. Data analysis and PDB depositions. P.L. and C.S-D. Cloning, protein production, data analysis. C.D.O. crystallization, crystallographic data collection and data analysis. E.F. Electrophilic fragment screening and intact protein mass spectrometry. P.A-B. and A.K. synthesis of heterocyclic electrophiles. G.M.K. heterocyclic electrophile library design and review of manuscript. T.D.D, J.D.F, S.P.J., H.F.K. and P.O.B. designed, synthesised and curated the York 3-D fragments. M.J.W. Conception and design of PepLite hits and data analysis. G.D. synthesis of PepLites and data analysis. M.E.M.N and M.P.M Analysis of PepLite crystal structures, data analysis and review of manuscript. A.A, J.B-N., A.C, A.D, L.D., M.F., R.S., M.S. and C.W. Resources and validation. All authors read and approved the manuscript.
Record Identifier: 993263156603596

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