Nature communications · 2020
Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Douangamath Alice, Fearon Daren, Gehrtz Paul, Krojer Tobias, Lukacik Petra, Owen C David, Resnick Efrat, Strain-Damerell Claire, Aimon Anthony, Ábrányi-Balogh Péter, Brandão-Neto José, Carbery Anna, Davison Gemma, Dias Alexandre, Downes Thomas D, Dunnett Louise, Fairhead Michael, Firth James D, Jones S Paul, Keeley Aaron, Keserü György M, Klein Hanna F, Martin Mathew P, Noble Martin E M, O'Brien Peter, Powell Ailsa, Reddi Rambabu N, Skyner Rachael, Snee Matthew, Waring Michael J, Wild Conor, London Nir, von Delft Frank, Walsh Martin A
Аннотация
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.