Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A

Science. 2021 Feb 26;371(6532):926-931. doi: 10.1126/science.abf4058. Epub 2021 Jan 25.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins interact with the eukaryotic translation machinery, and inhibitors of translation have potent antiviral effects. We found that the drug plitidepsin (aplidin), which has limited clinical approval, possesses antiviral activity (90% inhibitory concentration = 0.88 nM) that is more potent than remdesivir against SARS-CoV-2 in vitro by a factor of 27.5, with limited toxicity in cell culture. Through the use of a drug-resistant mutant, we show that the antiviral activity of plitidepsin against SARS-CoV-2 is mediated through inhibition of the known target eEF1A (eukaryotic translation elongation factor 1A). We demonstrate the in vivo efficacy of plitidepsin treatment in two mouse models of SARS-CoV-2 infection with a reduction of viral replication in the lungs by two orders of magnitude using prophylactic treatment. Our results indicate that plitidepsin is a promising therapeutic candidate for COVID-19.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate / analogs & derivatives
  • Adenosine Monophosphate / pharmacology
  • Adenosine Monophosphate / therapeutic use
  • Alanine / analogs & derivatives
  • Alanine / pharmacology
  • Alanine / therapeutic use
  • Animals
  • Antiviral Agents / pharmacology*
  • Antiviral Agents / therapeutic use
  • COVID-19 / drug therapy*
  • COVID-19 / prevention & control
  • COVID-19 / virology
  • Coronavirus Nucleocapsid Proteins / biosynthesis
  • Coronavirus Nucleocapsid Proteins / genetics
  • Depsipeptides / administration & dosage
  • Depsipeptides / pharmacology*
  • Depsipeptides / therapeutic use
  • Drug Evaluation, Preclinical
  • Female
  • HEK293 Cells
  • Humans
  • Lung / virology
  • Mice, Inbred C57BL
  • Mutation
  • Peptide Elongation Factor 1 / antagonists & inhibitors*
  • Peptides, Cyclic
  • Phosphoproteins / biosynthesis
  • Phosphoproteins / genetics
  • RNA, Viral / biosynthesis
  • RNA, Viral / genetics
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / genetics
  • SARS-CoV-2 / physiology
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Coronavirus Nucleocapsid Proteins
  • Depsipeptides
  • EEF1A1 protein, human
  • Peptide Elongation Factor 1
  • Peptides, Cyclic
  • Phosphoproteins
  • RNA, Viral
  • nucleocapsid phosphoprotein, SARS-CoV-2
  • remdesivir
  • Adenosine Monophosphate
  • Alanine
  • plitidepsin

Supplementary concepts

  • COVID-19 drug treatment