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From the same journal

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

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  • 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
  • S. Paul Jones
  • Aaron Keeley
  • György M. Keserü
  • Mathew P. Martin
  • Martin E.M. Noble
  • Ailsa Powell
  • Rambabu N. Reddi
  • Rachael Skyner
  • Matthew Snee
  • Michael J. Waring
  • Conor Wild
  • Nir London
  • Frank von Delft
  • Martin A. Walsh


Publication details

JournalNature Communications
DateAccepted/In press - 7 Sep 2020
DatePublished (current) - 7 Oct 2020
Issue number1
Original languageEnglish


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.

Bibliographical note

© 2020, The Author(s).

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