Pan-3C Protease Inhibitor Rupintrivir Binds SARS-CoV-2 Main Protease in a Unique Binding Mode.
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 (Mpro) 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.
Mesh Terms:
Antiviral Agents, Catalytic Domain, Coronavirus 3C Proteases, Crystallography, X-Ray, Cysteine Proteinase Inhibitors, Enterovirus D, Human, Hydrogen Bonding, Isoxazoles, Phenylalanine, Protein Binding, Pyrrolidinones, SARS-CoV-2, Static Electricity, Valine
Antiviral Agents, Catalytic Domain, Coronavirus 3C Proteases, Crystallography, X-Ray, Cysteine Proteinase Inhibitors, Enterovirus D, Human, Hydrogen Bonding, Isoxazoles, Phenylalanine, Protein Binding, Pyrrolidinones, SARS-CoV-2, Static Electricity, Valine
Biochemistry
Date: Oct. 05, 2021
PubMed ID: 34506130
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