Roles of the Picornaviral 3C Proteinase in the Viral Life Cycle and Host Cells

Sun, Di; Chen, Shun; Cheng, Anchun; Wang, Mingshu

Although covalent binding results in strong inhibition, the electrophilic nature of irreversible 3C pro inhibitors may increase off-target safety risks due to potential interactions with host cysteine proteases [135] . Thus, exploration of non-covalent inhibitors of picornaviral 3C pro s has already begun. Non-covalent inhibitors of RV 3C pro and CVB3 3C pro have been identified through fragment screening and FRET-based enzyme assay screening [136] . The chemical modification from water-insolubility to water-solubility shows a positive effect. Indeed, water-insoluble 3C pro inhibitors of CV B3 dissolved in 100% dimethyl sulfoxide (DMSO) have been reported to inhibit viral proliferation and to decrease myocardial damage and mortality in a chronic myocarditis model [137, 138] . With the exception of organic solvents, organic reagents exhibit potential as 3C pro inhibitors. Interaction between the cyanohydrins moiety and 3C pro catalytic site exhibits high selectivity and improved inhibitory activity [139] .