Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-020-18709-w
Keywords
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Categories
Funding
- Diamond MX group
- AstraZeneca
- Astex Pharmaceuticals
- Lilly
- Pfizer
- Vernalis
- University of York
- EU (Horizon 2020 program, Marie Skodowska-Curie grant) [675899]
- AbbVie [1097737]
- Bayer Pharma AG [1097737]
- Boehringer Ingelheim [1097737]
- Canada Foundation for Innovation [1097737]
- Eshelman Institute for Innovation [1097737]
- Genome Canada [1097737]
- Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant] [1097737, 115766]
- Janssen [1097737]
- Merck KGaA Darmstadt Germany [1097737]
- MSD [1097737]
- Novartis Pharma AG [1097737]
- Ontario Ministry of Economic Development and Innovation [1097737]
- Pfizer [1097737]
- Sao Paulo Research Foundation-FAPESP [1097737]
- Takeda [1097737]
- Wellcome [1097737, 106169/ZZ14/Z]
- Israel Science Foundation [2462/19]
- Israel Cancer Research Fund
- Israeli Ministry of Science Technology [3-14763]
- Moross Integrated Cancer Center
- Barry Sherman institute for Medicinal Chemistry
- Helen and Martin Kimmel Center for Molecular Design
- Joel and Mady Dukler Fund for Cancer Research
- Estate of Emile Mimran and Virgin JustGiving
- George Schwartzman Fund
- Foreign Commonwealth and Development Office (UK)
- Hungarian Science Foundation [PD124598]
- MRC [MR/M010937/1] Funding Source: UKRI
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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.
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