tetano
Editor, Senior Moderator
Nat Commun
. 2021 Oct 18;12(1):6055.
doi: 10.1038/s41467-021-26239-2.
Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19
Britton Boras[SUP] #[/SUP][SUP] 1 [/SUP], Rhys M Jones[SUP] #[/SUP][SUP] 2 [/SUP], Brandon J Anson[SUP] 3 [/SUP], Dan Arenson[SUP] 4 [/SUP], Lisa Aschenbrenner[SUP] 4 [/SUP], Malina A Bakowski[SUP] 5 [/SUP], Nathan Beutler[SUP] 6 [/SUP], Joseph Binder[SUP] 1 [/SUP], Emily Chen[SUP] 5 [/SUP], Heather Eng[SUP] 4 [/SUP], Holly Hammond[SUP] 7 [/SUP], Jennifer Hammond[SUP] 8 [/SUP], Robert E Haupt[SUP] 7 [/SUP], Robert Hoffman[SUP] 1 [/SUP], Eugene P Kadar[SUP] 4 [/SUP], Rob Kania[SUP] 1 [/SUP], Emi Kimoto[SUP] 4 [/SUP], Melanie G Kirkpatrick[SUP] 5 [/SUP], Lorraine Lanyon[SUP] 4 [/SUP], Emma K Lendy[SUP] 9 [/SUP], Jonathan R Lillis[SUP] 10 [/SUP], James Logue[SUP] 7 [/SUP], Suman A Luthra[SUP] 11 [/SUP], Chunlong Ma[SUP] 12 [/SUP], Stephen W Mason[SUP] 4 13 [/SUP], Marisa E McGrath[SUP] 7 [/SUP], Stephen Noell[SUP] 4 [/SUP], R Scott Obach[SUP] 4 [/SUP], Matthew N O' Brien[SUP] 14 [/SUP], Rebecca O'Connor[SUP] 4 [/SUP], Kevin Ogilvie[SUP] 4 [/SUP], Dafydd Owen[SUP] 11 [/SUP], Martin Pettersson[SUP] 11 [/SUP], Matthew R Reese[SUP] 4 [/SUP], Thomas F Rogers[SUP] 6 15 [/SUP], Romel Rosales[SUP] 16 17 [/SUP], Michelle I Rossulek[SUP] 11 [/SUP], Jean G Sathish[SUP] 13 [/SUP], Norimitsu Shirai[SUP] 4 [/SUP], Claire Steppan[SUP] 4 [/SUP], Martyn Ticehurst[SUP] 10 [/SUP], Lawrence W Updyke[SUP] 11 [/SUP], Stuart Weston[SUP] 7 [/SUP], Yuao Zhu[SUP] 13 [/SUP], Kris M White[SUP] 16 17 [/SUP], Adolfo García-Sastre[SUP] 16 17 [/SUP], Jun Wang[SUP] 12 [/SUP], Arnab K Chatterjee[SUP] 5 [/SUP], Andrew D Mesecar[SUP] 3 9 [/SUP], Matthew B Frieman[SUP] 7 [/SUP], Annaliesa S Anderson[SUP] 13 [/SUP], Charlotte Allerton[SUP] 11 [/SUP]
Affiliations
Abstract
COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.
. 2021 Oct 18;12(1):6055.
doi: 10.1038/s41467-021-26239-2.
Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19
Britton Boras[SUP] #[/SUP][SUP] 1 [/SUP], Rhys M Jones[SUP] #[/SUP][SUP] 2 [/SUP], Brandon J Anson[SUP] 3 [/SUP], Dan Arenson[SUP] 4 [/SUP], Lisa Aschenbrenner[SUP] 4 [/SUP], Malina A Bakowski[SUP] 5 [/SUP], Nathan Beutler[SUP] 6 [/SUP], Joseph Binder[SUP] 1 [/SUP], Emily Chen[SUP] 5 [/SUP], Heather Eng[SUP] 4 [/SUP], Holly Hammond[SUP] 7 [/SUP], Jennifer Hammond[SUP] 8 [/SUP], Robert E Haupt[SUP] 7 [/SUP], Robert Hoffman[SUP] 1 [/SUP], Eugene P Kadar[SUP] 4 [/SUP], Rob Kania[SUP] 1 [/SUP], Emi Kimoto[SUP] 4 [/SUP], Melanie G Kirkpatrick[SUP] 5 [/SUP], Lorraine Lanyon[SUP] 4 [/SUP], Emma K Lendy[SUP] 9 [/SUP], Jonathan R Lillis[SUP] 10 [/SUP], James Logue[SUP] 7 [/SUP], Suman A Luthra[SUP] 11 [/SUP], Chunlong Ma[SUP] 12 [/SUP], Stephen W Mason[SUP] 4 13 [/SUP], Marisa E McGrath[SUP] 7 [/SUP], Stephen Noell[SUP] 4 [/SUP], R Scott Obach[SUP] 4 [/SUP], Matthew N O' Brien[SUP] 14 [/SUP], Rebecca O'Connor[SUP] 4 [/SUP], Kevin Ogilvie[SUP] 4 [/SUP], Dafydd Owen[SUP] 11 [/SUP], Martin Pettersson[SUP] 11 [/SUP], Matthew R Reese[SUP] 4 [/SUP], Thomas F Rogers[SUP] 6 15 [/SUP], Romel Rosales[SUP] 16 17 [/SUP], Michelle I Rossulek[SUP] 11 [/SUP], Jean G Sathish[SUP] 13 [/SUP], Norimitsu Shirai[SUP] 4 [/SUP], Claire Steppan[SUP] 4 [/SUP], Martyn Ticehurst[SUP] 10 [/SUP], Lawrence W Updyke[SUP] 11 [/SUP], Stuart Weston[SUP] 7 [/SUP], Yuao Zhu[SUP] 13 [/SUP], Kris M White[SUP] 16 17 [/SUP], Adolfo García-Sastre[SUP] 16 17 [/SUP], Jun Wang[SUP] 12 [/SUP], Arnab K Chatterjee[SUP] 5 [/SUP], Andrew D Mesecar[SUP] 3 9 [/SUP], Matthew B Frieman[SUP] 7 [/SUP], Annaliesa S Anderson[SUP] 13 [/SUP], Charlotte Allerton[SUP] 11 [/SUP]
Affiliations
- PMID: 34663813
- DOI: 10.1038/s41467-021-26239-2
Abstract
COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.