1. Pan-3C Protease Inhibitor Rupintrivir Binds SARS-CoV-2 Main Protease in a Unique Binding Mode.
- Author
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Lockbaum GJ, Henes M, Lee JM, Timm J, Nalivaika EA, Thompson PR, Kurt Yilmaz N, and Schiffer CA
- Subjects
- Antiviral Agents chemistry, Catalytic Domain, Coronavirus 3C Proteases antagonists & inhibitors, Coronavirus 3C Proteases chemistry, Crystallography, X-Ray, Cysteine Proteinase Inhibitors chemistry, Enterovirus D, Human enzymology, Hydrogen Bonding, Isoxazoles chemistry, Phenylalanine chemistry, Phenylalanine metabolism, Protein Binding, Pyrrolidinones chemistry, Static Electricity, Valine chemistry, Valine metabolism, Antiviral Agents metabolism, Coronavirus 3C Proteases metabolism, Cysteine Proteinase Inhibitors metabolism, Isoxazoles metabolism, Phenylalanine analogs & derivatives, Pyrrolidinones metabolism, SARS-CoV-2 enzymology, Valine analogs & derivatives
- Abstract
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 Mpro splitting the catalytic cysteine and histidine residues. This bifurcation of the catalytic dyad may provide a novel approach for inhibiting cysteine proteases.- Published
- 2021
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