Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34663813.
- Also identified by DOI 10.1038/s41467-021-26239-2 and PMC identifier 8523698.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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.
Medical subject headings
- Coronavirus 3C Proteases
- Coronavirus Protease Inhibitors
- Indoles
- Leucine
- Pyrrolidinones
- COVID-19 Drug Treatment