1. A Comparative Analysis of SARS-CoV-2 Antivirals Characterizes 3CLpro Inhibitor PF-00835231 as a Potential New Treatment for COVID-19.
- Author
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de Vries, Maren, Mohamed, Adil S., Prescott, Rachel A., Valero-Jimenez, Ana M., Desvignes, Ludovic, O'Connor, Rebecca, Steppan, Claire, Devlin, Joseph C., Ivanova, Ellie, Herrera, Alberto, Schinlever, Austin, Loose, Paige, Ruggles, Kelly, Koralov, Sergei B., Anderson, Annaliesa S., Binder, Joseph, and Dittmann, Meike
- Subjects
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COVID-19 treatment , *COVID-19 , *SARS-CoV-2 , *ANTIVIRAL agents , *COMPARATIVE studies , *P-glycoprotein - Abstract
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 3CLpro (Mpro). The drug candidate PF-00835231 is the active compound of the first anti-3CLpro regimen in clinical trials. Here, we perform a comparative analysis of PF-00835231, the preclinical 3CLpro inhibitor GC-376, and the polymerase inhibitor remdesivir, in alveolar basal epithelial cells modified to express ACE2 (A5491ACE2 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 A5491ACE2 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 A5491ACE2 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 nonhuman in vitro models. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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