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Br J Pharmacol
. 2021 Apr 6.
doi: 10.1111/bph.15418. Online ahead of print.
Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS-CoV-2 infection in vitro
Sebastian Schloer 1 , Linda Brunotte 2 , Angeles Mecate-Zambrano 2 , Shuyu Zheng 3 , Jing Tang 3 , Stephan Ludwig 2 , Ursula Rescher 1
Affiliations
- PMID: 33825201
- DOI: 10.1111/bph.15418
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.