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