Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Coronavirus Protease Inhibitors/therapeutic use , Lactams/therapeutic use , Leucine/therapeutic use , Nitriles/therapeutic use , Proline/therapeutic use , Ritonavir/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , COVID-19/virology , Clinical Trials as Topic , Coronavirus Protease Inhibitors/administration & dosage , Coronavirus Protease Inhibitors/pharmacology , Cytidine/administration & dosage , Cytidine/analogs & derivatives , Cytidine/pharmacology , Cytidine/therapeutic use , Humans , Hydroxylamines/administration & dosage , Hydroxylamines/pharmacology , Hydroxylamines/therapeutic use , Lactams/administration & dosage , Lactams/pharmacology , Leucine/administration & dosage , Leucine/pharmacology , Nitriles/administration & dosage , Nitriles/pharmacology , Proline/administration & dosage , Proline/pharmacology , Ritonavir/administration & dosage , Ritonavir/pharmacology , SARS-CoV-2/drug effects , TabletsABSTRACT
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.