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A Comparative Analysis of SARS-CoV-2 Antivirals Characterizes 3CL(pro) Inhibitor PF-00835231 as a Potential New Treatment for COVID-19

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 comp...

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Autores principales: 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, Dittmann, Meike
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139662/
https://www.ncbi.nlm.nih.gov/pubmed/33622961
http://dx.doi.org/10.1128/JVI.01819-20
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author 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
Dittmann, Meike
author_facet 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
Dittmann, Meike
author_sort de Vries, Maren
collection PubMed
description 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 preclinical 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 nonhuman in vitro models. IMPORTANCE The arsenal of SARS-CoV-2 specific antiviral drugs is extremely limited. Only one direct-acting antiviral drug is currently approved, the viral polymerase inhibitor remdesivir, and it has limited efficacy. Thus, there is a substantial need to develop additional antiviral compounds with minimal side effects and alternate viral targets. One such alternate target is its main protease, 3CL(pro) (M(pro)), an essential component of the SARS-CoV-2 life cycle processing the viral polyprotein into the components of the viral polymerase complex. In this study, we characterize a novel antiviral drug, PF-00835231, which is the active component of the first-in-class 3CL(pro)-targeting regimen in clinical trials. Using 3D in vitro models of the human airway epithelium, we demonstrate the antiviral potential of PF-00835231 for inhibition of SARS-CoV-2.
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spelling pubmed-81396622021-06-14 A Comparative Analysis of SARS-CoV-2 Antivirals Characterizes 3CL(pro) Inhibitor PF-00835231 as a Potential New Treatment for COVID-19 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 Dittmann, Meike J Virol Vaccines and Antiviral Agents 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 preclinical 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 nonhuman in vitro models. IMPORTANCE The arsenal of SARS-CoV-2 specific antiviral drugs is extremely limited. Only one direct-acting antiviral drug is currently approved, the viral polymerase inhibitor remdesivir, and it has limited efficacy. Thus, there is a substantial need to develop additional antiviral compounds with minimal side effects and alternate viral targets. One such alternate target is its main protease, 3CL(pro) (M(pro)), an essential component of the SARS-CoV-2 life cycle processing the viral polyprotein into the components of the viral polymerase complex. In this study, we characterize a novel antiviral drug, PF-00835231, which is the active component of the first-in-class 3CL(pro)-targeting regimen in clinical trials. Using 3D in vitro models of the human airway epithelium, we demonstrate the antiviral potential of PF-00835231 for inhibition of SARS-CoV-2. American Society for Microbiology 2021-04-26 /pmc/articles/PMC8139662/ /pubmed/33622961 http://dx.doi.org/10.1128/JVI.01819-20 Text en Copyright © 2021 de Vries et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . https://doi.org/10.1128/ASMCopyrightv2This article is made available via the PMC Open Access Subset for unrestricted noncommercial re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
spellingShingle Vaccines and Antiviral Agents
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
Dittmann, Meike
A Comparative Analysis of SARS-CoV-2 Antivirals Characterizes 3CL(pro) Inhibitor PF-00835231 as a Potential New Treatment for COVID-19
title A Comparative Analysis of SARS-CoV-2 Antivirals Characterizes 3CL(pro) Inhibitor PF-00835231 as a Potential New Treatment for COVID-19
title_full A Comparative Analysis of SARS-CoV-2 Antivirals Characterizes 3CL(pro) Inhibitor PF-00835231 as a Potential New Treatment for COVID-19
title_fullStr A Comparative Analysis of SARS-CoV-2 Antivirals Characterizes 3CL(pro) Inhibitor PF-00835231 as a Potential New Treatment for COVID-19
title_full_unstemmed A Comparative Analysis of SARS-CoV-2 Antivirals Characterizes 3CL(pro) Inhibitor PF-00835231 as a Potential New Treatment for COVID-19
title_short A Comparative Analysis of SARS-CoV-2 Antivirals Characterizes 3CL(pro) Inhibitor PF-00835231 as a Potential New Treatment for COVID-19
title_sort comparative analysis of sars-cov-2 antivirals characterizes 3cl(pro) inhibitor pf-00835231 as a potential new treatment for covid-19
topic Vaccines and Antiviral Agents
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139662/
https://www.ncbi.nlm.nih.gov/pubmed/33622961
http://dx.doi.org/10.1128/JVI.01819-20
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