@article{db56c356ba20428ca391c4a369ee1cda,
title = "Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease",
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.",
author = "Alice Douangamath and Daren Fearon and Paul Gehrtz and Tobias Krojer and Petra Lukacik and Owen, {C. David} and Efrat Resnick and Claire Strain-Damerell and Anthony Aimon and P{\'e}ter {\'A}br{\'a}nyi-Balogh and Jos{\'e} Brand{\~a}o-Neto and Anna Carbery and Gemma Davison and Alexandre Dias and Downes, {Thomas D.} and Louise Dunnett and Michael Fairhead and Firth, {James D.} and Jones, {S. Paul} and Aaron Keeley and Keser{\"u}, {Gy{\"o}rgy M.} and Klein, {Hanna F.} and Martin, {Mathew P.} and Noble, {Martin E.M.} and Peter O{\textquoteright}Brien and Ailsa Powell and Reddi, {Rambabu N.} and Rachael Skyner and Matthew Snee and Waring, {Michael J.} and Conor Wild and Nir London and {von Delft}, Frank and Walsh, {Martin A.}",
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 Arag{\~a}o, 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 Sk{\l}odowska-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, S{\~a}o 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.",
year = "2020",
month = oct,
day = "7",
doi = "https://doi.org/10.1038/s41467-020-18709-w",
language = "الإنجليزيّة",
volume = "11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Research",
number = "1",
}