The SARS-CoV-2 main protease (M^pro): Structure, function, and emerging therapies for COVID-19

The main proteases (M^pro), also termed 3-chymotrypsin-like proteases (3CL^pro), are a class of highly conserved cysteine hydrolases in β-coronaviruses. Increasing evidence has demonstrated that 3CL^pros play an indispensable role in viral replication and have been recognized as key targets for preventing and treating coronavirus-caused infectious diseases, including COVID-19. This review is focused on the structural features and biological function of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease M^pro (also known as 3CL^pro), as well as recent advances in discovering and developing SARS-CoV-2 3CL^pro inhibitors. To better understand the characteristics of SARS-CoV-2 3CL^pro inhibitors, the inhibition activities, inhibitory mechanisms, and key structural features of various 3CL^pro inhibitors (including marketed drugs, peptidomimetic, and non-peptidomimetic synthetic compounds, as well as natural compounds and their derivatives) are summarized comprehensively. Meanwhile, the challenges in this field are highlighted, while future directions for designing and developing efficacious 3CL^pro inhibitors as novel anti-coronavirus therapies are also proposed. Collectively, all information and knowledge presented here are very helpful for understanding the structural features and inhibitory mechanisms of SARS-CoV-2 3CL^pro inhibitors, which offers new insights or inspiration to medicinal chemists for designing and developing more efficacious 3CL^pro inhibitors as novel anti-coronavirus agents.