Discovery of SARS-CoV-2 papain-like protease (PLpro) 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 M. Aschenbrenner; Amanda Balesano; Amin Behzadi; Britton W. Boras; Jeanne S. Chang; Heather F. Eng; Andrew Ephron; Timothy L. Foley; Kristen K. Ford; James M. Frick; Scott Gibson; Hao Li; Brett L. Hurst; Amit S.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

doi:10.1126/sciadv.ado4288

MicrobiologyScience AdvancesAug 30, 2024

Peer-reviewed journal article

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

Michelle R. Garnsey iD, Matthew C. Robinson iD, Luong T. Nguyen iD, Rhonda D. Cardin iD, Joseph Tillotson iD, Ellene H. Mashalidis iD, Aijia Yu, Lisa M. Aschenbrenner iD, Amanda Balesano iD, Amin Behzadi, Britton W. Boras iD, Jeanne S. Chang iD, Heather F. Eng iD, Andrew Ephron, Timothy L. Foley iD, Kristen K. Ford, James M. Frick, Scott Gibson, Hao Li iD, Brett L. Hurst iD, Amit S.S. Kalgutkar iD, Magdalena Korczynska iD, Zsofia Lengyel‐Zhand iD, Liping Gao iD, Hannah R. Meredith iD, , Alpha A. Lee iD

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 (PLpro) is one of two essential cysteine proteases involved in viral replication. While inhibitors of the SARS-CoV-2 main protease (Mpro) have demonstrated clinical efficacy, known PLpro inhibitors have to date lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PLpro 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 PLpro inhibitors, with lead compound PF-07957472 (4) providing robust efficacy in a mouse-adapted model of COVID-19 infection.

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