Why the study?
Despite being a pan-3C protease inhibitor, rupintrivir shows extremely weak activity against the homologous 3C-like protease of SARS-CoV-2.
Rupintrivir binds to SARS-CoV-2 Mpro in a unique conformation that bifurcates the catalytic dyad, suggesting a novel structural approach for inhibiting cysteine proteases.
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Preclinical binding data do not support clinical use of rupintrivir; leaves open a novel structural strategy for cysteine protease inhibition.
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.
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Lockbaum et al. (2021) studied this question.
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