Discovery of a Novel Inhibitor of Coronavirus 3CL Protease for the Potential Treatment of COVID-19

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.; Rossulek, Michelle I.; Sathish, Jean G.; Shirai, Norimitsu; Steppan, Claire; Ticehurst, Martyn; Updyke, Lawrence W.; Weston, Stuart; Zhu, Yuao; 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. The designed phosphate prodrug PF-07304814 is metabolized to PF-00835321 which is a potent inhibitor in vitro of the coronavirus family 3CL pro, with selectivity over human host protease targets. Furthermore, PF-00835231 exhibits potent in vitro antiviral activity against SARS-CoV-2 as a single agent and it is additive/synergistic in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of this compound as a potential COVID-19 treatment.