Structure-Based Optimization and Biological Evaluation of SARS-CoV-2 3CLpro Covalent Inhibitors

The global emergence of COVID-19, caused by SARS-CoV-2, has underscored the critical need for effective antivirals against coronaviruses. The 3-chymotrypsin-like protease (3CLpro) of coronavirus has been a primary target for drug development due to its critical role across various coronaviruses. Following our initial report, this study focuses on the structure-based optimization of 3CLpro covalent inhibitors. With the guidance of molecular docking and covalent binding parameters measured from an innovative isothermal titration calorimetry-kinetic competition (ITC-KC) assay, we optimized and synthesized series of potent covalent inhibitors with antiviral activity in cell-based assays.