Pan-3C Protease Inhibitor Rupintrivir Binds SARS-CoV-2 Main Protease in a Unique Binding Mode
Authors
Lockbaum, Gordon J.Henes, Mina
Lee, Jeong Min.
Timm, Jennifer
Nalivaika, Ellen A.
Thompson, Paul R
Yilmaz, Nese Kurt
Schiffer, Celia A.
UMass Chan Affiliations
Thompson LabSchiffer Lab
Department of Biochemistry and Molecular Pharmacology
Document Type
Journal ArticlePublication Date
2021-10-05Keywords
rupintrivir3C cysteine proteases
pan-3C protease inhibitor
SARS-CoV-2
Biochemistry
Chemistry
Enzymes and Coenzymes
Infectious Disease
Microbiology
Structural Biology
Virus Diseases
Viruses
Metadata
Show full item recordAbstract
Rupintrivir 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.Source
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
DOI
10.1021/acs.biochem.1c00414Permanent Link to this Item
http://hdl.handle.net/20.500.14038/27503PubMed ID
34506130Related Resources
ae974a485f413a2113503eed53cd6c53
10.1021/acs.biochem.1c00414