Advances in enzymatic activity regulation mechanism and inhibitor discovery of coronavirus 3C-like protease

Global pandemic caused by coronavirus remains a huge threat to public health. No efficacious drugs and vaccines are available so far. Therefore, it is urgent to design and develop anti-coronavirus clinical drugs. The 3C-like protease is a promising key drug target, as it plays a pivotal role in viral replication and is highly conserved in all coronaviruses. This review summarizes the major advances in the structure, catalytic mechanism, substrate specificity, auto-processing mechanism and inhibitor discovery for the 3C-like protease of SARS-CoV, MERS-CoV and SARS-CoV-2, classifies known inhibitors and analyzes their possible inhibition mechanisms. Potential future directions of 3C-like protease inhibitor discovery with novel mechanisms are also discussed.