Structural biology of SARS-CoV-2 M^pro and drug discovery

Since its outbreak in late 2019, the COVID-19 pandemic has drawn enormous attention worldwide as a consequence of being the most disastrous infectious disease in the past century. As one of the most immediately druggable targets of SARS-CoV-2, the main protease (M^pro) has been studied thoroughly. In this review, we provide a comprehensive summary of recent advances in structural studies of M^pro, which provide new knowledge about M^pro in terms of its biological function, structural characteristics, substrate specificity, and autocleavage process. We examine the remarkable strides made in targeting M^pro for drug discovery during the pandemic. We summarize insights into the current understanding of the structural features of M^pro and the discovery of existing M^pro-targeting drugs, illuminating pathways for the future development of anti-SARS-CoV-2 therapeutics.