Open AccessPan-3C Protease Inhibitor Rupintrivir Binds SARS-CoV-2 Main Protease in a Unique Binding Mode
Author(s) -
G.J. Lockbaum,
M. Henes,
Jeong Min Lee,
Jennifer Timm,
E.A. Nalivaika,
Paul R. Thompson,
Neşe Kurt Yılmaz,
Celia A. Schiffer
Publication year - 2021
Publication title -
biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.43
H-Index - 253
eISSN - 1520-4995
pISSN - 0006-2960
DOI - 10.1021/acs.biochem.1c00414
Subject(s) - proteases , protease , cysteine protease , picornavirus , cysteine , protein superfamily , chemistry , biochemistry , masp1 , picornaviridae , enzyme , serine protease , virology , biology , virus , enterovirus , rna , gene
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.
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