Perspectives on SARS-CoV-2 Main Protease Inhibitors.
Gao K, Wang R, Chen J, Tepe JJ, Huang F, Wei GW.
The main protease (M<sup>pro</sup>) plays a crucial role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication and is highly conserved, rendering it one of the most attractive therapeutic targets for SARS-CoV-2 inhibition. Currently, although two drug candidates targeting SARS-CoV-2 M<sup>pro</sup> designed by Pfizer are under clinical trials, no SARS-CoV-2 medication is approved due to the long period of drug development. Here, we collect a comprehensive list of 817 available SARS-CoV-2 and SARS-CoV M<sup>pro</sup> inhibitors from the literature or databases and analyze their molecular mechanisms of action. The structure-activity relationships (SARs) among each series of inhibitors are discussed. Additionally, we broadly examine available antiviral activity, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and animal tests of these inhibitors. We comment on their druggability or drawbacks that prevent them from becoming drugs. This Perspective sheds light on the future development of M<sup>pro</sup> inhibitors for SARS-CoV-2 and future coronavirus diseases.