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

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

6.2. Broad-Spectrum Inhibitors of 3C pro and 3CL pro 3C pro and 3C-like protease (3CL pro ) encoded by the Picornaviridae, Caliciviridae, and Coronaviridae families, are necessary for virus replication. Sharing a typical chymotrypsin-like fold, an extended binding site, a Cys-His-Glu/Asp catalytic triad (EV, CV 3C pro and NV 3C pro ) or Cys-His dyad (SARS-CoV 3CL pro ), and a cleavage preference at the Gln-Gly (P1-P1 1 ) junction, 3C pro and 3CL pro have been investigated as broad-spectrum antiviral targets, though 3C pro is a monomer and 3CL pro is a dimer [140] . The typical inhibitor of picornavirus 3C pro AG7088 fails to inhibit SARS-CoV 3CL pro due to subtle differences in the active site structures [141] . However, a modified AG7088 shows good inhibition of 3CL pro and no inhibition of 3C pro [142] . Using high-throughput screening, one compound that contains a central dihydropyrazole ring and four surrounding rings has been identified as equally inhibiting both the PV 3C pro and CoV 3CL pro [143] . By designing tripeptidyl transition state inhibitors and mimics, highly potent inhibitors that function against picornaviruses, coronaviruses and noroviruses have been discovered with minimal or no ability to inhibit a panel of proteases such as trypsin, thrombin or α-chymotrypsin [144] . The first macrocyclic inhibitor of 3C pro of CVB3, 3CL pro of SARS-CoV and 3CL pro of noroviruses has been reported, with inhibitory activities of 1.8, 15.5 and 5.1 µM, respectively [145] . Research on picornaviral 3C pro can provide a reference for other viruses.