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. The 3CL protease of SARS-CoV-2 is inhibited by PF-00835231 in vitro. Here, the authors show that the prodrug PF-07304814 has broad spectrum activity, inhibiting SARS-CoV and SARS-CoV-2 in mice and its ADME and safety profile support clinical development.
【저자키워드】 SARS-CoV-2, pharmacokinetics, Preclinical research, Pharmacodynamics, 【초록키워드】 COVID-19, Treatment, coronavirus, SARS-CoV, Human, Remdesivir, SARS-CoV-2 virus, protease, in vitro, antiviral activity, ADME, global pandemic, Protease inhibitor, Protein, clinical evaluation, mice, targets, selectivity, in vivo, 3CL, safety profile, Protease activity, prodrug, broad spectrum, Combination, phosphate, Support, clinical development, human host, PF-07304814, caused, inhibit, inhibited, exhibited, coronavirus, inhibiting, sustained, the SARS-CoV-2 virus, 【제목키워드】 COVID19, Protease inhibitor, 3CL, Potential treatment, intravenous, Preclinical,