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

  • bioRxiv. 2021 Feb 19:2020.08.28.272880. doi: 10.1101/2020.08.28.272880.
Maren de Vries  1 ,  Adil S Mohamed  1 ,  Rachel A Prescott  1  2 ,  Ana M Valero-Jimenez  1 ,  Ludovic Desvignes  3  4 ,  Rebecca O'Connor  5 ,  Claire Steppan  5 ,  Joseph C Devlin  2  6 ,  Ellie Ivanova  7 ,  Alberto Herrera  7 ,  Austin Schinlever  1  2 ,  Paige Loose  1 ,  Kelly Ruggles  6 ,  Sergei B Koralov  7 ,  Annaliesa S Anderson  8 ,  Joseph Binder  9 ,  Meike Dittmann  1
Affiliations
  • 1. Department of Microbiology, New York University Grossman School of Medicine, New York 10016, USA.
  • 2. Vilcek Institute of Graduate Biomedical Sciences, New York University Grossman School of Medicine, New York 10016, USA.
  • 3. Department of Medicine, New York University Grossman School of Medicine, New York 10016, USA.
  • 4. Office of Science & Research, NYU Langone Health, New York 10016, USA.
  • 5. Pfizer Discovery Sciences, Groton, CT 06340, USA.
  • 6. Institute of Systems Genetics, New York University Grossman School of Medicine, New York 10016, USA.
  • 7. Department of Pathology, New York University Grossman School of Medicine, New York 10016, USA.
  • 8. Pfizer Vaccine Research and Development, Pearl River, NY 10695, USA.
  • 9. Pfizer Oncology Research and Development, San Diego, CA 92128, USA.
PMID: 32869028 DOI: 10.1101/2020.08.28.272880
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 pre-clinical 3CLpro 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.

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