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

共 50 条

[1] Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2
Klemm, Theresa
Ebert, Gregor
Calleja, Dale J.
Allison, Cody C.
Richardson, Lachlan W.
Bernardini, Jonathan P.
Lu, Bernadine G. C.
Kuchel, Nathan W.
Grohmann, Christoph
Shibata, Yuri
Gan, Zhong Yan
Cooney, James P.
Doerflinger, Marcel
Au, Amanda E.
Blackmore, Timothy R.
van der Heden van Noort, Gerbrand J.
Geurink, Paul P.
Ovaa, Huib
Newman, Janet
Riboldi-Tunnicliffe, Alan
Czabotar, Peter E.
Mitchell, Jeffrey P.
Feltham, Rebecca
Lechtenberg, Bernhard C.
Lowes, Kym N.
Dewson, Grant
Pellegrini, Marc
Lessene, Guillaume
Komander, David
EMBO JOURNAL, 2020, 39 (18):
[2] Understanding the active site of the SARS-CoV-2 papain-like protease (PLPro)
Balogun, MaryAgnes
Wu, Amy Wu
Bacorn, Mickayla
Olivas, Cassandra
Zardecki, Christine
Lubin, Joseph
Khare, Sagar
Burley, Stephen
ACTA CRYSTALLOGRAPHICA A-FOUNDATION AND ADVANCES, 2021, 77 : A311 - A311
[3] Identification of SARS-CoV-2 Papain-like Protease (PLpro) Inhibitors Using Combined Computational Approach
Sencanski, Milan
Perovic, Vladimir
Milicevic, Jelena
Todorovic, Tamara
Prodanovic, Radivoje
Veljkovic, Veljko
Paessler, Slobodan
Glisic, Sanja
CHEMISTRYOPEN, 2022, 11 (02):
[4] Identification of Triazolopyrimidinyl Scaffold SARS-CoV-2 Papain-Like Protease (PLpro) Inhibitor
Kralj, Sebastjan
Jukic, Marko
Bahun, Miha
Kranjc, Luka
Kolaric, Anja
Hodoscek, Milan
Ulrih, Natasa Poklar
Bren, Urban
PHARMACEUTICS, 2024, 16 (02)
[5] Genetically Encoded Fluorescent Sensors for SARS-CoV-2 Papain-like Protease PLpro
Sokolinskaya, Elena L.
Putlyaeva, Lidia, V
Polinovskaya, Vasilisa S.
Lukyanov, Konstantin A.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2022, 23 (14)
[6] Fragment-Based Screen of SARS-CoV-2 Papain-like Protease (PLpro)
Taylor, Ashley J.
Amporndanai, Kangsa
Rietz, Tyson A.
Zhao, Bin
Thiruvaipati, Anusha
Wei, Qiangqiang
South, Taylor M.
Crow, Mackenzie M.
Apakama, Chideraa
Sensintaffar, John L.
Phan, Jason
Lee, Taekyu
Fesik, Stephen W.
ACS MEDICINAL CHEMISTRY LETTERS, 2024, 15 (08): : 1351 - 1357
[7] Discovery of a reversible covalent inhibitor against Papain-like protease (PLpro) from SARS-CoV-2 virus
Bajaj, Teena
Wehri, Eddie
Suryawanshi, Rahul
Pardeshi, Kundan
King, Elizabeth
Behrouzi, Kamyar
Khodabakshi, Zahra
Kumar, G. Renuka
Mofrad, Mohammad R. K.
Nomura, Daniel K.
Ott, Melanie
Schaltesky, Julia
Murthy, Niren
PROTEIN SCIENCE, 2023, 32
[8] Large-Scale Virtual Screening for the Discovery of SARS-CoV-2 Papain-like Protease (PLpro) Non-covalent Inhibitors
Garland, Olivia
Ton, Anh-Tien
Moradi, Shoeib
Smith, Jason R.
Kovacic, Suzana
Ng, Kurtis
Pandey, Mohit
Ban, Fuqiang
Lee, Jaeyong
Vuckovic, Marija
Worrall, Liam J.
Young, Robert N.
Pantophlet, Ralph
Strynadka, Natalie C. J.
Cherkasov, Artem
JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2023, 63 (07) : 2158 - 2169
[9] Validation and Invalidation of SARS-CoV-2 Papain-like Protease Inhibitors
Ma, Chunlong
Wang, Jun
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE, 2022, 5 (02) : 102 - 109
[10] A Patent Review on SARS Coronavirus Papain-Like Protease (PLpro) Inhibitors
Chia, C. S. Brian
Lim, Siew Pheng
CHEMMEDCHEM, 2023, 18 (16)

← 1 2 3 4 5 →