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

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

  • Sci Adv. 2024 Aug 30;10(35):eado4288. doi: 10.1126/sciadv.ado4288.
Michelle R Garnsey 1,  Matthew C Robinson 2,  Luong T Nguyen 2,  Rhonda Cardin 3,  Joseph Tillotson 1,  Ellene Mashalidis 4,  Aijia Yu 5,  Lisa Aschenbrenner 4,  Amanda Balesano 4,  Amin Behzadi 3,  Britton Boras 6,  Jeanne S Chang 4,  Heather Eng 4,  Andrew Ephron 4,  Tim Foley 4,  Kristen K Ford 4,  James M Frick 2,  Scott Gibson 7,  Li Hao 3,  Brett Hurst 7,  Amit S Kalgutkar 1,  Magdalena Korczynska 1,  Zsofia Lengyel-Zhand 4,  Liping Gao 5,  Hannah R Meredith 1,  Nandini C Patel 1,  Jana Polivkova 4,  Devendra Rai 4,  Colin R Rose 4,  Hussin Rothan 3,  Sylvie K Sakata 6,  Thomas R Vargo 2,  Wenying Qi 5,  Huixian Wu 4,  Yiping Liu 5,  Irina Yurgelonis 3,  Jinzhi Zhang 8,  Yuao Zhu 3,  Lei Zhang 1,  Alpha A Lee 2
Affiliations

Affiliations

  • 1 Pfizer Global Research and Development, Cambridge, MA 02139, USA.
  • 2 PostEra, 1 Broadway, 14th floor, Cambridge, MA 02142, USA.
  • 3 Pfizer Global Research and Development, Pearl River, NY 10965, USA.
  • 4 Pfizer Global Research and Development, Groton, CT 06340, USA.
  • 5 WuXi, WuXi AppTec (Shanghai) Co. Ltd. Shanghai 200131, China.
  • 6 Pfizer Global Research and Development, La Jolla, CA 92121, USA.
  • 7 Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences,Utah State University, Logan, UT 84322, USA.
  • 8 Pfizer Global Research and Development, Shanghai 201210, China.
PMID: 39213347 DOI: 10.1126/sciadv.ado4288
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 (PLpro) 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.

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