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.
