Discovery of SARS-CoV-2 papain-like protease (PLpro) 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...

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Published inbioRxiv
Main Authors Garnsey, Michelle R, Robinson, Matthew C, Nguyen, Luong T, Cardin, Rhonda, Tillotson, Joseph, Mashalidis, Ellene, Yu Aijia, Aschenbrenner, Lisa, Balesano, Amanda, Behzadi, Amin, Boras, Britton, Chang, Jeanne S, Eng, Heather, Ephron, Andrew, Foley, Tim, d, Kristen, Frick, James M, Gibson, Scott, Li, Hao, Hurst, Brett, Kalgutkar, Amit S, Korczynska, Magdalena, Lengyel-Zhand, Zsofia, Gao Liping, Meredith, Hannah R, Patel, Nandini C, Polivkova, Jana, Rai, Devendra, Rose, Colin R, Rothan, Hussin, Sakata, Sylvie K, Vargo, Thomas R, Qi, Wenying, Wu, Huixian, Liu, Yiping, Yurgelonis, Irina, Zhang, Jinzhi, Zhu, Yuao, Zhang, Lei, Lee, Alpha A
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 13.02.2024
Subjects
Antiviral agents
Coronaviruses
COVID-19
Drug development
Papain
Pharmacokinetics
Proteinase
Proteinase inhibitors
Severe acute respiratory syndrome coronavirus 2
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Summary: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.Competing Interest StatementSome authors are employees of Pfizer Inc and PostEra Inc, companies with commercial interests in the discovery, development and commercialization of therapeutics, including antivirals directed at SARS-CoV-2.Footnotes* Formatting updates
DOI:10.1101/2024.01.26.577395