Advances in research on 3C-like protease (3CL pro ) inhibitors against SARS-CoV-2 since 2020.

COVID-19 caused by SARS-CoV-2 in late 2019 is still threatening global human health. Although some vaccines and drugs are available in the market, controlling the spread of the SARS-CoV-2 virus remains a huge challenge. 3C-like protease (3CL pro ) is a highly conserved key protease for SARS-CoV-2 replication, and no relevant homologous protein with a similar cleavage site to 3CL pro has been identified in humans, highlighting that development of 3CL pro inhibitors exhibits great promise for treatment of COVID-19. In this review, the authors describe the structure and function of 3CL pro . To better understand the characteristics of SARS-CoV-2 3CL pro inhibitors, the SARS-CoV-2 3CL pro inhibitors reported since 2020 are classified into peptidomimetic covalent inhibitors, non-peptidomimetic covalent inhibitors and non-covalent small molecule inhibitors, and the representative inhibitors, their biological activities and binding models are highlighted. Collectively, we hope that all the information presented here will provide new insights into the design and development of more effective 3CL pro inhibitors against SARS-CoV-2 as novel anti-coronavirus drugs.