Discovery of SARS-CoV-2 papain-like protease (PL <sup>pro</sup> ) inhibitors with efficacy in a murine infection model
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<sup>pro</sup>) 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 PL<sup>pro</sup> inhibitors have, to date, lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PL<sup>pro</sup> 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 PL<sup>pro</sup> inhibitors, with lead compound PF-07957472 (<b>4</b>) providing robust efficacy in a mouse-adapted model of COVID-19 infection.
Authors
- Magdalena Korczynska (ORCID: https://orcid.org/0000-0002-1339-5553)
- Yuao Zhu (ORCID: https://orcid.org/0000-0001-9831-6836)
- Nandini C. Patel (ORCID: https://orcid.org/0000-0002-2735-7662)
- Aijia Yu
- Brett L. Hurst (ORCID: https://orcid.org/0000-0003-1025-5878)
- Rhonda D. Cardin (ORCID: https://orcid.org/0000-0003-2390-8591)
- Heather Eng (ORCID: https://orcid.org/0000-0002-2914-3967)
- Jana Polívková (ORCID: https://orcid.org/0009-0002-4011-9447)
- Liping Gao (ORCID: https://orcid.org/0000-0002-7022-0418)
- Amanda Balesano (ORCID: https://orcid.org/0009-0001-7641-1127)
- Thomas R. Vargo (ORCID: https://orcid.org/0009-0003-4203-5754)
- Britton Boras (ORCID: https://orcid.org/0000-0003-3624-9177)
- Kristen K. Ford
- Irina Yurgelonis (ORCID: https://orcid.org/0009-0003-2081-7907)
- Matthew C. Robinson (ORCID: https://orcid.org/0009-0001-3935-9083)
- Jeanne S. Chang (ORCID: https://orcid.org/0000-0002-8043-8621)
- Sylvie K. Sakata (ORCID: https://orcid.org/0009-0003-2314-3979)
- Joseph Tillotson (ORCID: https://orcid.org/0000-0003-0795-5494)
- Colin R. Rose
- Huixian Wu (ORCID: https://orcid.org/0000-0003-1357-9747)
- Ellene H. Mashalidis (ORCID: https://orcid.org/0000-0001-7435-2306)
- James M. Frick
- Wenying Qi (ORCID: https://orcid.org/0009-0002-4328-7008)
- Hao Li (ORCID: https://orcid.org/0000-0002-8865-7351)
- Lisa Aschenbrenner (ORCID: https://orcid.org/0009-0005-2921-068X)
- Zsofia Lengyel‐Zhand (ORCID: https://orcid.org/0000-0001-8447-8631)
- Alpha A. Lee (ORCID: https://orcid.org/0000-0002-9616-3108)
- Hussin A. Rothan (ORCID: https://orcid.org/0000-0002-7300-6388)
- Michelle R. Garnsey (ORCID: https://orcid.org/0000-0003-1226-1868)
- Jinzhi Zhang (ORCID: https://orcid.org/0009-0009-7198-2535)
- Luong T. Nguyen (ORCID: https://orcid.org/0000-0002-9686-3112)
- Timothy L. Foley (ORCID: https://orcid.org/0000-0002-5987-5253)
- Hannah R. Meredith (ORCID: https://orcid.org/0000-0002-5315-7568)
- Devendra Rai (ORCID: https://orcid.org/0000-0001-5606-2364)
- Amit S.S. Kalgutkar (ORCID: https://orcid.org/0000-0001-9701-756X)
- Andrew Ephron
- Lei Zhang (ORCID: https://orcid.org/0000-0001-8118-1402)
- Yiping Liu (ORCID: https://orcid.org/0000-0001-7974-4587)
- Amin Behzadi
- Scott Gibson
Institutions
- Broad Institute (US)
- Utah State University (US)
- Pfizer (United States) (US)
- WuXi AppTec (China) (CN)
- Pfizer (China) (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2024-08-30
- DOI
- https://doi.org/10.1126/sciadv.ado4288
- Citations
- 42
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 16.34