Discovery of SARS-CoV-2 papain-like protease (PL <sup>pro</sup> ) inhibitors with efficacy in a murine infection model
Michelle R. Garnsey, Matthew C. Robinson, Luong T. Nguyen, Rhonda D. Cardin, Joseph Tillotson, Ellene H. Mashalidis, Aijia Yu, Lisa Aschenbrenner, Amanda Balesano, Amin Behzadi, Britton Boras, Jeanne S. Chang, Heather Eng, Andrew Ephron, Timothy L. Foley, Kristen K. Ford, James M. Frick, Scott Gibson, Hao Li, Brett L. Hurst, Amit S. Kalgutkar, Magdalena Korczynska, Zsofia Lengyel‐Zhand, Liping Gao, Hannah R. Meredith, Nandini C. Patel, Jana Polívková, Devendra Rai, Colin R. Rose, Hussin A. Rothan, Sylvie K. Sakata, Thomas R. Vargo, Wenying Qi, Huixian Wu, Yiping Liu, Irina Yurgelonis, Jinzhi Zhang, Yuao Zhu, Lei Zhang, Alpha A. Lee
Abstract
Vaccines and first-generation antiviral therapeutics have provided important protection against 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 the two essential cysteine proteases involved in viral replication. While inhibitors of the SARS-CoV-2 main protease 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. Here, 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.