Journal Article

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

García-Sastre, Adolfo, Logue, James, Anson, Brandon J., Lendy, Emma K., Haupt, Robert E., McGrath, Marisa E., Chatterjee, Arnab K., Kadar, Eugene P., Bakowski, Malina A., Arenson, Dan, Ma, Chunlong, Sathish, Jean G., Boras, Britton, Hammond, Holly, Frieman, Matthew B., O’ Brien, Matthew N., O’Connor, Rebecca, Lillis, Jonathan R., Ogilvie, Kevin, Noell, Stephen, Allerton, Charlotte, Pettersson, Martin, Mesecar, Andrew D., Zhu, Yuao, White, Kris M., Hoffman, Robert, Kania, Rob, Updyke, Lawrence W., Weston, Stuart, Obach, R. Scott, Hammond, Jennifer, Steppan, Claire, Eng, Heather, Luthra, Suman A., Chen, Emily, Rossulek, Michelle I., Rogers, Thomas F., Ticehurst, Martyn, Reese, Matthew R., Owen, Dafydd, Shirai, Norimitsu, Rosales, Romel, Anderson, Annaliesa S., Aschenbrenner, Lisa, Kirkpatrick, Melanie G., Wang, Jun, Kimoto, Emi, Binder, Joseph, Jones, Rhys M., Lanyon, Lorraine, Mason, Stephen W., Beutler, Nathan

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 14 / 14/34 / 631/154/436/1729 / 631/154/436/2388 / 631/326/596/4130 / 692/308/2778 / Adenosine Monophosphate - administration & dosage / Adenosine Monophosphate - adverse effects / Adenosine Monophosphate - analogs & derivatives / Adenosine Monophosphate - pharmacokinetics / Alanine - administration & dosage / Alanine - adverse effects / Alanine - analogs & derivatives / Alanine - pharmacokinetics / Animals / Antiviral activity / Antiviral drugs / Chlorocebus aethiops / Coronavirus 229E, Human - drug effects / Coronavirus 229E, Human - enzymology / Coronavirus 3C Proteases - antagonists & inhibitors / Coronavirus Protease Inhibitors - administration & dosage / Coronavirus Protease Inhibitors - adverse effects / Coronavirus Protease Inhibitors - pharmacokinetics / Coronaviruses / COVID-19 / COVID-19 - virology / COVID-19 Drug Treatment / Disease Models, Animal / Drug Design / Drug Synergism / Drug Therapy, Combination / HeLa Cells / Humanities and Social Sciences / Humans / Indoles - administration & dosage / Indoles - adverse effects / Indoles - pharmacokinetics / Infusions, Intravenous / Intravenous administration / Leucine - administration & dosage / Leucine - adverse effects / Leucine - pharmacokinetics / Mice / multidisciplinary / Pandemics / Prodrugs / Protease / Protease inhibitors / Proteinase inhibitors / Pyrrolidinones - administration & dosage / Pyrrolidinones - adverse effects / Pyrrolidinones - pharmacokinetics / Safety / SARS-CoV-2 - drug effects / SARS-CoV-2 - enzymology / Science / Science (multidisciplinary) / Selectivity / Severe acute respiratory syndrome coronavirus 2 / Severe acute respiratory syndrome-related coronavirus - drug effects / Severe acute respiratory syndrome-related coronavirus - enzymology / Vero Cells / Viral diseases