Discovery of SARS-CoV-2 papain-like protease (PL ^pro ) inhibitors with efficacy in a murine infection model

Vaccines and first-generation antiviral therapeutics have provided important protection against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PL ^pro ) is one of two essential cysteine proteases involved in viral replication. While inhibitors of the SARS-CoV-2 main protease (M ^pro ) have demonstrated clinical efficacy, known PL ^pro inhibitors have to date lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PL ^pro translates to in vivo efficacy in a preclinical setting. Herein, we report the machine learning-driven discovery of potent, selective, and orally available SARS-CoV-2 PL ^pro inhibitors, with lead compound PF-07957472 ( 4 ) providing robust efficacy in a mouse-adapted model of COVID-19 infection.