Design, synthesis, and binding analysis of target-specific covalent inhibitors of SARS-CoV-2 papain-like protease

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The global emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 2019 resulted in widespread consequences for human health, with an ongoing situation six years later. Despite extensive efforts, the virus continues to circulate, resulting in a persistent rate of new diagnoses and fatalities. The potential for future outbreaks is heightened by the emergence of new mutations, underscoring the need for effective additional treatment options, such as antiviral drugs, to prevent the difficulties experienced during the COVID-19 pandemic. In this study, a structure-guided ligand design strategy was applied to optimize the SARS-CoV-2 papain-like protease (PL pro ) inhibitor GRL0617 and enhance its potency. A series of covalent inhibitors was synthesized, and their inhibition potential, target-specificity, binding mode, and selectivity against several human proteases were evaluated. Two compounds, LS 22-5 and AZ 23-6 , demonstrating the nanomolar inhibition potential of PL pro , were identified as lead compounds for antiviral drug design.