Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS-CoV-2 infection in vitro

Br J Pharmacol. 2021 Jun;178(11):2339-2350. doi: 10.1111/bph.15418. Epub 2021 Apr 6.

Abstract

Background and purpose: The SARS-COV-2 pandemic and the global spread of coronavirus disease 2019 (COVID-19) urgently call for efficient and safe antiviral treatment strategies. A straightforward approach to speed up drug development at lower costs is drug repurposing. Here, we investigated the therapeutic potential of targeting the interface of SARS CoV-2 with the host via repurposing of clinically licensed drugs and evaluated their use in combinatory treatments with virus- and host-directed drugs in vitro.

Experimental approach: We tested the antiviral potential of the antifungal itraconazole and the antidepressant fluoxetine on the production of infectious SARS-CoV-2 particles in the polarized Calu-3 cell culture model and evaluated the added benefit of a combinatory use of these host-directed drugs with the direct acting antiviral remdesivir, an inhibitor of viral RNA polymerase.

Key results: Drug treatments were well-tolerated and potently impaired viral replication. Importantly, both itraconazole-remdesivir and fluoxetine-remdesivir combinations inhibited the production of infectious SARS-CoV-2 particles > 90% and displayed synergistic effects, as determined in commonly used reference models for drug interaction.

Conclusion and implications: Itraconazole-remdesivir and fluoxetine-remdesivir combinations are promising starting points for therapeutic options to control SARS-CoV-2 infection and severe progression of COVID-19.

Keywords: SARS-CoV-2; combination therapy; drug repurposing; fluoxetine; itraconazole; remdesivir.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate / analogs & derivatives
  • Alanine / analogs & derivatives
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use
  • COVID-19 Drug Treatment*
  • Fluoxetine / pharmacology
  • Hepatitis C, Chronic* / drug therapy
  • Humans
  • Itraconazole / pharmacology
  • Pharmaceutical Preparations*
  • SARS-CoV-2

Substances

  • Antiviral Agents
  • Pharmaceutical Preparations
  • Fluoxetine
  • Itraconazole
  • remdesivir
  • Adenosine Monophosphate
  • Alanine