Reversible covalent inhibitors suppress enterovirus 71 infection by targeting the 3C protease

As one of the principal etiological agents of hand, foot, and mouth disease (HFMD), enterovirus 71 (EV71) is associated with severe neurological complications or fatal diseases, while without effective medications thus far. Here we applied dually activated Michael acceptor to develop a series of reversible covalent compounds for EV71 3C protease (3C(pro)), a promising antiviral drug target that plays an essential role during viral replication by cleaving the precursor polyprotein, inhibiting host protein synthesis, and evading innate immunity. Among them, cyanoacrylate and Boc-protected cyanoarylamide derivatives (SLQ-4 and SLQ-5) showed effective antiviral activity against EV71. The two inhibitors exhibited broad antiviral effects, acting on RD, 293T, and Vero cell lines, as well as on EV71 A, B, C, CVA16, and CVB3 viral strains. We further determined the binding pockets between the two inhibitors and 3C(pro) based on docking studies. These results, together with our previous studies, provide evidence to elucidate the mechanism of action of these two reversible covalent inhibitors and contribute to the development of clinically effective medicines to treat EV71 infections.

Automated summary

This study demonstrated the effective antiviral activity of cyanoacrylate and Boc-protected cyanoarylamide derivatives as inhibitors against EV71, showing broad antiviral effects across various cell lines and viral strains. The binding pockets between these inhibitors and 3C(pro) were elucidated through docking studies, providing valuable insights for the development of clinically effective medicines to treat EV71 infections.