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.