1. Discovery of SARS-CoV-2 papain-like protease (PL pro ) inhibitors with efficacy in a murine infection model.
- Author
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Garnsey MR, Robinson MC, Nguyen LT, Cardin R, Tillotson J, Mashalidis E, Yu A, Aschenbrenner L, Balesano A, Behzadi A, Boras B, Chang JS, Eng H, Ephron A, Foley T, Ford KK, Frick JM, Gibson S, Hao L, Hurst B, Kalgutkar AS, Korczynska M, Lengyel-Zhand Z, Gao L, Meredith HR, Patel NC, Polivkova J, Rai D, Rose CR, Rothan H, Sakata SK, Vargo TR, Qi W, Wu H, Liu Y, Yurgelonis I, Zhang J, Zhu Y, Zhang L, and Lee AA
- Subjects
- Animals, Mice, Humans, COVID-19 virology, Protease Inhibitors pharmacology, Protease Inhibitors chemistry, Protease Inhibitors therapeutic use, Coronavirus 3C Proteases antagonists & inhibitors, Coronavirus 3C Proteases metabolism, Machine Learning, Female, Virus Replication drug effects, SARS-CoV-2 drug effects, COVID-19 Drug Treatment, Antiviral Agents pharmacology, Antiviral Agents chemistry, Antiviral Agents pharmacokinetics, Antiviral Agents therapeutic use, Disease Models, Animal, Coronavirus Papain-Like Proteases antagonists & inhibitors, Coronavirus Papain-Like Proteases metabolism
- 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 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. Here, 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.- Published
- 2024
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