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

  1. Alice Douangamath
  2. Daren Fearon
  3. Paul Gehrtz
  4. Tobias Krojer
  5. Petra Lukacik
  6. C. David Owen
  7. Efrat Resnick
  8. Claire Strain-Damerell
  9. Anthony Aimon
  10. Péter Ábrányi-Balogh
  11. José Brandaõ-Neto
  12. Anna Carbery
  13. Gemma Davison
  14. Alexandre Dias
  15. Thomas D Downes
  16. Louise Dunnett
  17. Michael Fairhead
  18. James D. Firth
  19. S. Paul Jones
  20. Aaron Keely
  21. György M. Keserü
  22. Hanna F Klein
  23. Mathew P. Martin
  24. Martin E. M. Noble
  25. Peter O’Brien
  26. Ailsa Powell
  27. Rambabu Reddi
  28. Rachael Skyner
  29. Matthew Snee
  30. Michael J. Waring
  31. Conor Wild
  32. Nir London
  33. Frank von Delft
  34. Martin A. Walsh
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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 was 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.

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