tetano
Editor, Senior Moderator
J Virol
. 2021 Feb 23;JVI.01819-20.
doi: 10.1128/JVI.01819-20. Online ahead of print.
A comparative analysis of SARS-CoV-2 antivirals characterizes 3CL [SUP]pro[/SUP] inhibitor PF-00835231 as a potential new treatment for COVID-19
Maren de Vries[SUP] 1 [/SUP], Adil S Mohamed[SUP] 1 [/SUP], Rachel A Prescott[SUP] 1 2 [/SUP], Ana M Valero-Jimenez[SUP] 1 [/SUP], Ludovic Desvignes[SUP] 3 4 [/SUP], Rebecca O'Connor[SUP] 5 [/SUP], Claire Steppan[SUP] 5 [/SUP], Joseph C Devlin[SUP] 2 6 [/SUP], Ellie Ivanova[SUP] 7 [/SUP], Alberto Herrera[SUP] 7 [/SUP], Austin Schinlever[SUP] 1 2 [/SUP], Paige Loose[SUP] 1 [/SUP], Kelly Ruggles[SUP] 6 [/SUP], Sergei B Koralov[SUP] 7 [/SUP], Annaliesa S Anderson[SUP] 8 [/SUP], Joseph Binder[SUP] 9 [/SUP], Meike Dittmann[SUP] 10 [/SUP]
Affiliations
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 3CL[SUP]pro[/SUP] (M[SUP]pro[/SUP]). The drug candidate PF-00835231 is the active compound of the first anti-3CL[SUP]pro[/SUP] regimen in clinical trials. Here, we perform a comparative analysis of PF-00835231, the pre-clinical 3CL[SUP]pro[/SUP] inhibitor GC-376, and the polymerase inhibitor remdesivir, in alveolar basal epithelial cells modified to express ACE2 (A549[SUP]+ACE2[/SUP] 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[SUP]+ACE2[/SUP] 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[SUP]+ACE2[/SUP] 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.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[SUP]pro[/SUP] (M[SUP]pro[/SUP]), 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[SUP]pro[/SUP]-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.
. 2021 Feb 23;JVI.01819-20.
doi: 10.1128/JVI.01819-20. Online ahead of print.
A comparative analysis of SARS-CoV-2 antivirals characterizes 3CL [SUP]pro[/SUP] inhibitor PF-00835231 as a potential new treatment for COVID-19
Maren de Vries[SUP] 1 [/SUP], Adil S Mohamed[SUP] 1 [/SUP], Rachel A Prescott[SUP] 1 2 [/SUP], Ana M Valero-Jimenez[SUP] 1 [/SUP], Ludovic Desvignes[SUP] 3 4 [/SUP], Rebecca O'Connor[SUP] 5 [/SUP], Claire Steppan[SUP] 5 [/SUP], Joseph C Devlin[SUP] 2 6 [/SUP], Ellie Ivanova[SUP] 7 [/SUP], Alberto Herrera[SUP] 7 [/SUP], Austin Schinlever[SUP] 1 2 [/SUP], Paige Loose[SUP] 1 [/SUP], Kelly Ruggles[SUP] 6 [/SUP], Sergei B Koralov[SUP] 7 [/SUP], Annaliesa S Anderson[SUP] 8 [/SUP], Joseph Binder[SUP] 9 [/SUP], Meike Dittmann[SUP] 10 [/SUP]
Affiliations
- PMID: 33622961
- DOI: 10.1128/JVI.01819-20
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 3CL[SUP]pro[/SUP] (M[SUP]pro[/SUP]). The drug candidate PF-00835231 is the active compound of the first anti-3CL[SUP]pro[/SUP] regimen in clinical trials. Here, we perform a comparative analysis of PF-00835231, the pre-clinical 3CL[SUP]pro[/SUP] inhibitor GC-376, and the polymerase inhibitor remdesivir, in alveolar basal epithelial cells modified to express ACE2 (A549[SUP]+ACE2[/SUP] 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[SUP]+ACE2[/SUP] 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[SUP]+ACE2[/SUP] 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.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[SUP]pro[/SUP] (M[SUP]pro[/SUP]), 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[SUP]pro[/SUP]-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.