Pathology

Enzyme

In vivo

Virus

Disease

Antiviral drug

Coronavirus disease 2019 (COVID-19)

Infectious disease (medical specialty)

ADME

Biology

Prodrug

Viral load

Virology

Chemistry

Protease

In vitro

Coronavirus

Antiretroviral therapy

Drug

Protease inhibitor (pharmacology)

Genetics

Biochemistry

Medicine

Pharmacology

Nature Communications

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.

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