Combination therapy with fluoxetine and the nucleoside analogue GS-441524 shows synergistic antiviral effects against various SARS-CoV-2 variants in vitro

Complete original article: Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro81 /

Authors: Linda Brunotte, Shuyu Zheng, Angeles Mecate-Zambrano, Jing Tang, Stephan Ludwig, Ursula Rescher, and Sebastian Schloer


The ongoing SARS-CoV-2 pandemic requires effective and safe antiviral treatment strategies. Drug repurposing is a fast and inexpensive approach to developing new treatment options. The direct antiviral agent remdesivir was found to have antiviral activity against SARS-CoV-2. While remdesivir has only a very short half-life and bioactivation, which depends on prodrug activating enzymes, its plasma metabolite GS-441524 can be activated by various kinases, including adenosine kinase (ADK), which is moderately expressed in all tissues. The pharmacokinetics of GS-441524 suggest that it is a suitable antiviral drug that can be administered to patients with COVID-19. In this work, we analyzed the antiviral properties of combination therapy with the metabolite remdesivir GS-441524 and the antidepressant fluoxetine in a polarized Calu-3 cell culture model against SARS-CoV-2. Combination therapy with GS-441524 and fluoxetine was well tolerated and showed synergistic antiviral effects against the three circulating SARS-CoV-2 variants in vitro in commonly used drug interaction reference models. Thus, combination treatment with GS-441524 virus-targeted and host-targeted fluoxetine could offer a suitable therapeutic option for the treatment of SARS-CoV-2 infections.

Translator's note: Fluoxetine is produced under various trade names, of which Prozac is probably the best known.

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