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 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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Douangamath A,Fearon D,Gehrtz P,Krojer T,Lukacik P,Owen CD,Resnick E,Strain-Damerell C,Aimon A,Ábrányi-Balogh P,Brandão-Neto J,Carbery A,Davison G,Dias A,Downes TD,Dunnett L,Fairhead M,Firth JD,Jones SP,Keeley A,Kdoi
10.1038/s41467-020-18709-wsubject
Has Abstractpub_date
2020-10-07 00:00:00pages
5047issue
1issn
2041-1723pii
10.1038/s41467-020-18709-wjournal_volume
11pub_type
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