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

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…

• IC
  Israel Cancer Research Fund
• EL
  Eli Lilly and Company
• P
  Pfizer
• A
  AstraZeneca
• GC
  Genome Canada

  Award: 115766
• MK
  Merck KGaA
• DL
  Diamond Light Source

  Award: 1097737
• EF
  European Federation of Pharmaceutical Industries and Associations

  Award: 115766
• AP
  Astex Pharmaceuticals
• OM
  Ontario Ministry of Economic Development and Innovation
• FD
  Fundação de Amparo à Pesquisa do Estado de São Paulo
• IS
  Israel Science Foundation

  Award: 2462/19
• MD
  Ministero dello Sviluppo Economico
• HS
  Hungarian Science Foundation

  Award: PD124598
• NP
  Novartis Pharma
• MR
  Medical Research Council

  Award: MR/M010937/1
• HA
  Helen and Martin Kimmel Center for Molecular Design, Weizmann Institute of Science