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
  • 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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