Discovery of a Novel Inhibitor of Coronavirus 3CL Protease for the Potential Treatment of COVID-19

Autor:	Emma K. Lendy, Martyn D. Ticehurst, Robert Steven Kania, Lisa Aschenbrenner, Chuang Ma, Michelle Rossulek, Emily I. Chen, Charlotte Moira Norfor Allerton, Rhys M. Jones, Stephen W. Mason, Kevin Ogilvie, Heather Eng, Dan Arenson, Lorraine F. Lanyon, Abhishek Chatterjee, Rob Haupt, Martin Pettersson, Britton Boras, Eugene P. Kadar, Malina A. Bakowski, Yuao Zhu, Obach Rs, Suman Luthra, Stuart Weston, Joseph John Binder, Lillis, Stephen Noell, Thomas F. Rogers, Dafydd R. Owen, O’Brien Mn, Claire M. Steppan, Lawrence W. Updyke, Jennifer Hammond, Jun Wang, Norimitsu Shirai, Brandon J. Anson, Nathan Beutler, Jean G. Sathish, Melanie G. Kirkpatrick, Annaliesa S. Anderson, James Logue, Matthew B. Frieman, Andrew D. Mesecar, Holly L. Hammond, Robert M. Hoffman, Reese Mr, Marisa McGrath, Rebecca E. O’Connor, Emi Kimoto
Rok vydání:	2020
Předmět:	Protease Coronavirus disease 2019 (COVID-19) SARS-CoV-2 Chemistry medicine.medical_treatment Prodrug medicine.disease_cause Virology Article In vitro Virus Pharmacodynamics Preclinical research In vivo medicine Pharmacokinetics ADME Coronavirus
Zdroj:	Nature Communications
DOI:	10.1101/2020.09.12.293498
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::84bedafdf92a23451d3e8b9574a30f85 https://doi.org/10.1101/2020.09.12.293498 Zobrazit plný text záznamu