Pan-3C Protease Inhibitor Rupintrivir Binds SARS-CoV-2 Main Protease in a Unique Binding Mode
AuthorsLockbaum, Gordon J.
Lee, Jeong Min.
Nalivaika, Ellen A.
Thompson, Paul R
Yilmaz, Nese Kurt
Schiffer, Celia A.
UMass Chan AffiliationsThompson Lab
Department of Biochemistry and Molecular Pharmacology
Document TypeJournal Article
3C cysteine proteases
pan-3C protease inhibitor
Enzymes and Coenzymes
MetadataShow full item record
AbstractRupintrivir targets the 3C cysteine proteases of the picornaviridae family, which includes rhinoviruses and enteroviruses that cause a range of human diseases. Despite being a pan-3C protease inhibitor, rupintrivir activity is extremely weak against the homologous 3C-like protease of SARS-CoV-2. In this study, the crystal structures of rupintrivir were determined bound to enterovirus 68 (EV68) 3C protease and the 3C-like main protease (M(pro)) from SARS-CoV-2. While the EV68 3C protease-rupintrivir structure was similar to previously determined complexes with other picornavirus 3C proteases, rupintrivir bound in a unique conformation to the active site of SARS-CoV-2 M(pro) splitting the catalytic cysteine and histidine residues. This bifurcation of the catalytic dyad may provide a novel approach for inhibiting cysteine proteases.
Lockbaum GJ, Henes M, Lee JM, Timm J, Nalivaika EA, Thompson PR, Kurt Yilmaz N, Schiffer CA. Pan-3C Protease Inhibitor Rupintrivir Binds SARS-CoV-2 Main Protease in a Unique Binding Mode. Biochemistry. 2021 Oct 5;60(39):2925-2931. doi: 10.1021/acs.biochem.1c00414. Epub 2021 Sep 10. PMID: 34506130; PMCID: PMC8457326. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/27503