Journal
ACS INFECTIOUS DISEASES
Volume 7, Issue 9, Pages 2591-2595Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.1c00237
Keywords
SARS-CoV-2; Mpro; protease; virology
Categories
Funding
- Massachusetts Consortium for Pathogen Readiness
- Howard Hughes Medical Institute
- Nancy Lurie Marks Family Foundation
- NIH [P30 GM 124165]
- DOE Office of Science [DE-AC02-06CH11357]
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The main protease (Mpro) of SARS-CoV-2 plays a key role in viral replication by cleaving viral polyproteins at specific sites, and its interactions with substrates can have significant effects on catalytic efficiency. The study provides insights into potential targets for antiviral drug design and highlights the importance of finely tuned substrate-dependent catalytic parameters in the coronavirus lifecycle.
The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease (COVID-19), is an ideal target for pharmaceutical inhibition. Mpro is conserved among coronaviruses and distinct from human proteases. Viral replication depends on the cleavage of the viral polyprotein at multiple sites. We present crystal structures of SARS-CoV-2 Mpro bound to two viral sub-strate peptides. The structures show how Mpro recognizes distinct substrates and how subtle changes in substrate accommodation can drive large changes in catalytic efficiency. One peptide, constituting the junction between viral nonstructural proteins 8 and 9 (nsp8/9), has P1' and P2' residues that are unique among the SARS-CoV-2 Mpro cleavage sites but conserved among homologous junctions in coronaviruses. Mpro cleaves nsp8/9 inefficiently, and amino acid substitutions at P1' or P2' can enhance catalysis. Visualization of Mpro with intact substrates provides new templates for antiviral drug design and suggests that the coronavirus lifecycle selects for finely tuned substrate-dependent catalytic parameters.
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