Discovery of SARS-CoV-2 papain-like protease (PL pro ) inhibitors with efficacy in a murine infection model
Year: 2024
Type: article
Abstract: 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.
Source: Science Advances
Authors: Michelle R. Garnsey, Matthew C. Robinson, Luong T. Nguyen, Rhonda Cardin, Joseph Tillotson, Ellene Mashalidis, Aijia Yu, Lisa Aschenbrenner, Amanda Balesano, Amin Behzadi, Britton Boras, Jeanne S. Chang, Heather Eng, Andrew Ephron, Tim Foley, Kristen K. Ford, James M. Frick, Scott Gibson, Li Hao, Brett Hurst, Amit S. Kalgutkar, Magdalena Korczynska, Zsofia Lengyel-Zhand, Liping Gao, Hannah R. Meredith, Nandini C. Patel, Jana Polivkova, Devendra Rai, Colin R. Rose, Hussin Rothan, Sylvie K. Sakata, Thomas R. Vargo, Wenying Qi, Huixian Wu, Yiping Liu, Irina Yurgelonis, Jinzhi Zhang, Yuao Zhu, Lei Zhang, Alpha A. Lee
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,500
OpenAlex ID: W4402039601