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 (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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antiviral Agents / chemistry
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Antiviral Agents / metabolism*
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Catalytic Domain
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Coronavirus 3C Proteases / antagonists & inhibitors
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Coronavirus 3C Proteases / chemistry
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Coronavirus 3C Proteases / metabolism*
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Crystallography, X-Ray
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Cysteine Proteinase Inhibitors / chemistry
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Cysteine Proteinase Inhibitors / metabolism*
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Enterovirus D, Human / enzymology
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Hydrogen Bonding
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Isoxazoles / chemistry
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Isoxazoles / metabolism*
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Phenylalanine / analogs & derivatives*
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Phenylalanine / chemistry
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Phenylalanine / metabolism
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Protein Binding
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Pyrrolidinones / chemistry
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Pyrrolidinones / metabolism*
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SARS-CoV-2 / enzymology*
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Static Electricity
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Valine / analogs & derivatives*
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Valine / chemistry
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Valine / metabolism
Substances
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Antiviral Agents
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Cysteine Proteinase Inhibitors
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Isoxazoles
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Pyrrolidinones
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Phenylalanine
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3C-like proteinase, SARS-CoV-2
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Coronavirus 3C Proteases
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Valine
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rupintrivir