Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19.

Boras, Britton; Jones, Rhys M; Anson, Brandon J; Arenson, Dan; Aschenbrenner, Lisa; Bakowski, Malina A; Beutler, Nathan; Binder, Joseph; Chen, Emily; Eng, Heather; Hammond, Holly; Hammond, Jennifer; Haupt, Robert E; Hoffman, Robert; Kadar, Eugene P; Kania, Rob; Kimoto, Emi; Kirkpatrick, Melanie G; Lanyon, Lorraine; Lendy, Emma K; Lillis, Jonathan R; Logue, James; Luthra, Suman A; Ma, Chunlong; Mason, Stephen W; McGrath, Marisa E; Noell, Stephen; Obach, R Scott; O' Brien, Matthew N; O'Connor, Rebecca; Ogilvie, Kevin; Owen, Dafydd; Pettersson, Martin; Reese, Matthew R; Rogers, Thomas F; Rosales, Romel; Rossulek, Michelle I; Sathish, Jean G; Shirai, Norimitsu; Steppan, Claire; Ticehurst, Martyn; Updyke, Lawrence W; Weston, Stuart; Zhu, Yuao; White, Kris M; García-Sastre, Adolfo; Wang, Jun; Chatterjee, Arnab K; Mesecar, Andrew D; Frieman, Matthew B; Anderson, Annaliesa S; Allerton, Charlotte

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.