Antiviral activity and safety of remdesivir against SARS-CoV-2 infection in human pluripotent stem cell-derived cardiomyocytes

Antiviral Res. 2020 Dec;184:104955. doi: 10.1016/j.antiviral.2020.104955. Epub 2020 Oct 19.

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is considered as the most significant global public health crisis of the century. Several drug candidates have been suggested as potential therapeutic options for COVID-19, including remdesivir, currently the only authorized drug for use under an Emergency Use Authorization. However, there is only limited information regarding the safety profiles of the proposed drugs, in particular drug-induced cardiotoxicity. Here, we evaluated the antiviral activity and cardiotoxicity of remdesivir using cardiomyocytes-derived from human pluripotent stem cells (hPSC-CMs) as an alternative source of human primary cardiomyocytes (CMs). In this study, remdesivir exhibited up to 60-fold higher antiviral activity in hPSC-CMs compared to Vero E6 cells; however, it also induced moderate cardiotoxicity in these cells. To gain further insight into the drug-induced arrhythmogenic risk, we assessed QT interval prolongation and automaticity of remdesivir-treated hPSC-CMs using a multielectrode array (MEA). As a result, the data indicated a potential risk of QT prolongation when remdesivir is used at concentrations higher than the estimated peak plasma concentration. Therefore, we conclude that close monitoring of the electrocardiographic/QT interval should be advised in SARS-CoV-2-infected patients under remdesivir medication, in particular individuals with pre-existing heart conditions.

Keywords: COVID-19; Human cardiomyocytes; Pluripotent stem cells; Remdesivir; SARS-CoV-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate / analogs & derivatives*
  • Adenosine Monophosphate / pharmacology
  • Alanine / analogs & derivatives*
  • Alanine / pharmacology
  • Amides / pharmacology
  • Animals
  • Antimalarials / pharmacology
  • Antiviral Agents / pharmacology*
  • COVID-19 / complications
  • COVID-19 / drug therapy
  • COVID-19 / virology*
  • Chlorocebus aethiops
  • Chloroquine / pharmacology
  • Electrocardiography
  • Flow Cytometry
  • Heart Diseases / complications
  • Humans
  • Hydroxychloroquine / pharmacology
  • Microscopy, Fluorescence
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / virology*
  • Pluripotent Stem Cells / cytology*
  • Pluripotent Stem Cells / virology
  • Pyrazines / pharmacology
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • SARS-CoV-2 / drug effects*
  • Vero Cells
  • Viral Plaque Assay

Substances

  • Amides
  • Antimalarials
  • Antiviral Agents
  • Pyrazines
  • remdesivir
  • Adenosine Monophosphate
  • Hydroxychloroquine
  • Chloroquine
  • favipiravir
  • Alanine