tetano
Editor, Senior Moderator
Sci Adv
. 2024 Aug 30;10(35):eado4288.
doi: 10.1126/sciadv.ado4288. Epub 2024 Aug 30. Discovery of SARS-CoV-2 papain-like protease (PL[SUP]pro[/SUP]) inhibitors with efficacy in a murine infection model
Michelle R Garnsey[SUP] 1 [/SUP], Matthew C Robinson[SUP] 2 [/SUP], Luong T Nguyen[SUP] 2 [/SUP], Rhonda Cardin[SUP] 3 [/SUP], Joseph Tillotson[SUP] 1 [/SUP], Ellene Mashalidis[SUP] 4 [/SUP], Aijia Yu[SUP] 5 [/SUP], Lisa Aschenbrenner[SUP] 4 [/SUP], Amanda Balesano[SUP] 4 [/SUP], Amin Behzadi[SUP] 3 [/SUP], Britton Boras[SUP] 6 [/SUP], Jeanne S Chang[SUP] 4 [/SUP], Heather Eng[SUP] 4 [/SUP], Andrew Ephron[SUP] 4 [/SUP], Tim Foley[SUP] 4 [/SUP], Kristen K Ford[SUP] 4 [/SUP], James M Frick[SUP] 2 [/SUP], Scott Gibson[SUP] 7 [/SUP], Li Hao[SUP] 3 [/SUP], Brett Hurst[SUP] 7 [/SUP], Amit S Kalgutkar[SUP] 1 [/SUP], Magdalena Korczynska[SUP] 1 [/SUP], Zsofia Lengyel-Zhand[SUP] 4 [/SUP], Liping Gao[SUP] 5 [/SUP], Hannah R Meredith[SUP] 1 [/SUP], Nandini C Patel[SUP] 1 [/SUP], Jana Polivkova[SUP] 4 [/SUP], Devendra Rai[SUP] 4 [/SUP], Colin R Rose[SUP] 4 [/SUP], Hussin Rothan[SUP] 3 [/SUP], Sylvie K Sakata[SUP] 6 [/SUP], Thomas R Vargo[SUP] 2 [/SUP], Wenying Qi[SUP] 5 [/SUP], Huixian Wu[SUP] 4 [/SUP], Yiping Liu[SUP] 5 [/SUP], Irina Yurgelonis[SUP] 3 [/SUP], Jinzhi Zhang[SUP] 8 [/SUP], Yuao Zhu[SUP] 3 [/SUP], Lei Zhang[SUP] 1 [/SUP], Alpha A Lee[SUP] 2 [/SUP]
Affiliations
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 (4) providing robust efficacy in a mouse-adapted model of COVID-19 infection.
. 2024 Aug 30;10(35):eado4288.
doi: 10.1126/sciadv.ado4288. Epub 2024 Aug 30. Discovery of SARS-CoV-2 papain-like protease (PL[SUP]pro[/SUP]) inhibitors with efficacy in a murine infection model
Michelle R Garnsey[SUP] 1 [/SUP], Matthew C Robinson[SUP] 2 [/SUP], Luong T Nguyen[SUP] 2 [/SUP], Rhonda Cardin[SUP] 3 [/SUP], Joseph Tillotson[SUP] 1 [/SUP], Ellene Mashalidis[SUP] 4 [/SUP], Aijia Yu[SUP] 5 [/SUP], Lisa Aschenbrenner[SUP] 4 [/SUP], Amanda Balesano[SUP] 4 [/SUP], Amin Behzadi[SUP] 3 [/SUP], Britton Boras[SUP] 6 [/SUP], Jeanne S Chang[SUP] 4 [/SUP], Heather Eng[SUP] 4 [/SUP], Andrew Ephron[SUP] 4 [/SUP], Tim Foley[SUP] 4 [/SUP], Kristen K Ford[SUP] 4 [/SUP], James M Frick[SUP] 2 [/SUP], Scott Gibson[SUP] 7 [/SUP], Li Hao[SUP] 3 [/SUP], Brett Hurst[SUP] 7 [/SUP], Amit S Kalgutkar[SUP] 1 [/SUP], Magdalena Korczynska[SUP] 1 [/SUP], Zsofia Lengyel-Zhand[SUP] 4 [/SUP], Liping Gao[SUP] 5 [/SUP], Hannah R Meredith[SUP] 1 [/SUP], Nandini C Patel[SUP] 1 [/SUP], Jana Polivkova[SUP] 4 [/SUP], Devendra Rai[SUP] 4 [/SUP], Colin R Rose[SUP] 4 [/SUP], Hussin Rothan[SUP] 3 [/SUP], Sylvie K Sakata[SUP] 6 [/SUP], Thomas R Vargo[SUP] 2 [/SUP], Wenying Qi[SUP] 5 [/SUP], Huixian Wu[SUP] 4 [/SUP], Yiping Liu[SUP] 5 [/SUP], Irina Yurgelonis[SUP] 3 [/SUP], Jinzhi Zhang[SUP] 8 [/SUP], Yuao Zhu[SUP] 3 [/SUP], Lei Zhang[SUP] 1 [/SUP], Alpha A Lee[SUP] 2 [/SUP]
Affiliations
- PMID: 39213347
- PMCID: PMC11364104
- DOI: 10.1126/sciadv.ado4288
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 (4) providing robust efficacy in a mouse-adapted model of COVID-19 infection.