A comparative analysis of SARS-CoV-2 antivirals in human airway models characterizes 3CL pro inhibitor PF-00835231 as a potential new treatment for COVID-19.

Autor:	de Vries M; Department of Microbiology, New York University Grossman School of Medicine, New York 10016, USA., Mohamed AS; Department of Microbiology, New York University Grossman School of Medicine, New York 10016, USA., Prescott RA; Department of Microbiology, New York University Grossman School of Medicine, New York 10016, USA.; Vilcek Institute of Graduate Biomedical Sciences, New York University Grossman School of Medicine, New York 10016, USA., Valero-Jimenez AM; Department of Microbiology, New York University Grossman School of Medicine, New York 10016, USA., Desvignes L; Department of Medicine, New York University Grossman School of Medicine, New York 10016, USA.; Office of Science & Research, NYU Langone Health, New York 10016, USA., O'Connor R; Pfizer Discovery Sciences, Groton, CT 06340, USA., Steppan C; Pfizer Discovery Sciences, Groton, CT 06340, USA., Devlin JC; Vilcek Institute of Graduate Biomedical Sciences, New York University Grossman School of Medicine, New York 10016, USA.; Institute of Systems Genetics, New York University Grossman School of Medicine, New York 10016, USA., Ivanova E; Department of Pathology, New York University Grossman School of Medicine, New York 10016, USA., Herrera A; Department of Pathology, New York University Grossman School of Medicine, New York 10016, USA., Schinlever A; Department of Microbiology, New York University Grossman School of Medicine, New York 10016, USA.; Vilcek Institute of Graduate Biomedical Sciences, New York University Grossman School of Medicine, New York 10016, USA., Loose P; Department of Microbiology, New York University Grossman School of Medicine, New York 10016, USA., Ruggles K; Institute of Systems Genetics, New York University Grossman School of Medicine, New York 10016, USA., Koralov SB; Department of Pathology, New York University Grossman School of Medicine, New York 10016, USA., Anderson AS; Pfizer Vaccine Research and Development, Pearl River, NY 10695, USA., Binder J; Pfizer Oncology Research and Development, San Diego, CA 92128, USA., Dittmann M; Department of Microbiology, New York University Grossman School of Medicine, New York 10016, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2021 Feb 19. Date of Electronic Publication: 2021 Feb 19.
DOI:	10.1101/2020.08.28.272880
Abstrakt:	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of Coronavirus Disease 2019 (COVID-19). There is a dire need for novel effective antivirals to treat COVID-19, as the only approved direct-acting antiviral to date is remdesivir, targeting the viral polymerase complex. A potential alternate target in the viral life cycle is the main SARS-CoV-2 protease 3CL pro (M pro ). The drug candidate PF-00835231 is the active compound of the first anti-3CL pro regimen in clinical trials. Here, we perform a comparative analysis of PF-00835231, the pre-clinical 3CL pro inhibitor GC-376, and the polymerase inhibitor remdesivir, in alveolar basal epithelial cells modified to express ACE2 (A549 +ACE2 cells). We find PF-00835231 with at least similar or higher potency than remdesivir or GC-376. A time-of-drug-addition approach delineates the timing of early SARS-CoV-2 life cycle steps in A549 +ACE2 cells and validates PF-00835231's early time of action. In a model of the human polarized airway epithelium, both PF-00835231 and remdesivir potently inhibit SARS-CoV-2 at low micromolar concentrations. Finally, we show that the efflux transporter P-glycoprotein, which was previously suggested to diminish PF-00835231's efficacy based on experiments in monkey kidney Vero E6 cells, does not negatively impact PF-00835231 efficacy in either A549 +ACE2 cells or human polarized airway epithelial cultures. Thus, our study provides in vitro evidence for the potential of PF-00835231 as an effective SARS-CoV-2 antiviral and addresses concerns that emerged based on prior studies in non-human in vitro models. Competing Interests: Competing interests M. D. received a contract from Pfizer Inc. to support the studies reported herein. These authors are employees of Pfizer Inc. and hold stock in Pfizer Inc: Joseph Binder, Annaliesa Anderson, Claire Steppan, Rebecca O’Connor.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu