Discovery of SARS-CoV-2 papain-like protease (PL <sup>pro</sup> ) inhibitors with efficacy in a murine infection model-Reference-Cited by-同舟云学术

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

Published:2024-08-30 Issue:35 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Garnsey Michelle R.¹^ORCID,Robinson Matthew C.²^ORCID,Nguyen Luong T.²,Cardin Rhonda³^ORCID,Tillotson Joseph¹^ORCID,Mashalidis Ellene⁴,Yu Aijia⁵^ORCID,Aschenbrenner Lisa⁴^ORCID,Balesano Amanda⁴^ORCID,Behzadi Amin³^ORCID,Boras Britton⁶^ORCID,Chang Jeanne S.⁴^ORCID,Eng Heather⁴^ORCID,Ephron Andrew⁴^ORCID,Foley Tim⁴^ORCID,Ford Kristen K.⁴^ORCID,Frick James M.²^ORCID,Gibson Scott⁷,Hao Li³^ORCID,Hurst Brett⁷^ORCID,Kalgutkar Amit S.¹^ORCID,Korczynska Magdalena¹^ORCID,Lengyel-Zhand Zsofia⁴,Gao Liping⁵,Meredith Hannah R.¹^ORCID,Patel Nandini C.¹^ORCID,Polivkova Jana⁴^ORCID,Rai Devendra⁴,Rose Colin R.⁴,Rothan Hussin³,Sakata Sylvie K.⁶^ORCID,Vargo Thomas R.²^ORCID,Qi Wenying⁵^ORCID,Wu Huixian⁴^ORCID,Liu Yiping⁵,Yurgelonis Irina³^ORCID,Zhang Jinzhi⁸^ORCID,Zhu Yuao³^ORCID,Zhang Lei¹^ORCID,Lee Alpha A.²^ORCID

Affiliation:

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.

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 PL pro inhibitors have, to date, lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PL pro 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 pro inhibitors, with lead compound PF-07957472 ( 4 ) providing robust efficacy in a mouse-adapted model of COVID-19 infection.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.ado4288

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