Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease
Summary
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 was 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.
Competing Interest Statement
The authors have declared no competing interest.
Subject Area
- Biochemistry (11703)
- Bioengineering (8722)
- Bioinformatics (29127)
- Biophysics (14932)
- Cancer Biology (12048)
- Cell Biology (17359)
- Clinical Trials (138)
- Developmental Biology (9406)
- Ecology (14143)
- Epidemiology (2067)
- Evolutionary Biology (18268)
- Genetics (12220)
- Genomics (16766)
- Immunology (11841)
- Microbiology (28005)
- Molecular Biology (11552)
- Neuroscience (60808)
- Paleontology (450)
- Pathology (1864)
- Pharmacology and Toxicology (3231)
- Physiology (4939)
- Plant Biology (10384)
- Synthetic Biology (2877)
- Systems Biology (7333)
- Zoology (1642)