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

被引：4

作者：

Garnsey, Michelle R. ^{[1
]}

Robinson, Matthew C. ^{[2
]}

Nguyen, Luong T. ^{[2
]}

Cardin, Rhonda ^{[3
]}

Tillotson, Joseph ^{[1
]}

Mashalidis, Ellene ^{[4
]}

Yu, Aijia ^{[5
]}

Aschenbrenner, Lisa ^{[4
]}

Balesano, Amanda ^{[4
]}

Behzadi, Amin ^{[3
]}

Boras, Britton ^{[6
]}

Chang, Jeanne S. ^{[4
]}

Eng, Heather ^{[4
]}

Ephron, Andrew ^{[4
]}

Foley, Tim ^{[4
]}

Ford, Kristen K. ^{[4
]}

Frick, James M. ^{[2
]}

Gibson, Scott ^{[7
]}

Hao, Li ^{[3
]}

Hurst, Brett ^{[7
]}

Kalgutkar, Amit S. ^{[1
]}

Korczynska, Magdalena ^{[1
]}

Lengyel-Zhand, Zsofia ^{[4
]}

Gao, Liping ^{[5
]}

Meredith, Hannah R. ^{[1
]}

Patel, Nandini C. ^{[1
]}

Polivkova, Jana ^{[4
]}

Rai, Devendra ^{[4
]}

Rose, Colin R. ^{[4
]}

Rothan, Hussin ^{[3
]}

Sakata, Sylvie K. ^{[6
]}

Vargo, Thomas R. ^{[2
]}

Qi, Wenying ^{[5
]}

Wu, Huixian ^{[4
]}

Liu, Yiping ^{[5
]}

Yurgelonis, Irina ^{[3
]}

Zhang, Jinzhi ^{[8
]}

Zhu, Yuao ^{[3
]}

Zhang, Lei ^{[1
]}

Lee, Alpha A. ^{[2
]}

机构：

[1] Pfizer Global Res & Dev, Cambridge, MA 02139 USA

[2] PostEra, 1 Broadway,14th Floor, Cambridge, MA 02142 USA

[3] Pfizer Global Res & Dev, Pearl River, NY 10965 USA

[4] Pfizer Global Res & Dev, Groton, CT 06340 USA

[5] WuXi AppTec Shanghai Co, Shanghai 200131, Peoples R China

[6] Pfizer Global Res & Dev, La Jolla, CA 92121 USA

[7] Utah State Univ, Inst Antiviral Res, Dept Anim Dairy & Vet Sci, Logan, UT 84322 USA

[8] Pfizer Global Res & Dev, Shanghai 201210, Peoples R China

来源：

SCIENCE ADVANCES | 2024年 / 10卷 / 35期

关键词：

46;

D O I：

10.1126/sciadv.ado4288

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：10

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