Combination Therapy with Fluoxetine and the Nucleoside Analog GS-441524 Exerts Synergistic Antiviral Effects against Different SARS-CoV-2 Variants In Vitro.

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

doi:10.3390/pharmaceutics13091400

Linda Brunotte, Jing Tang + Show 5 more

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https://doi.org/10.3390/pharmaceutics13091400

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Abstract

The ongoing SARS-CoV-2 pandemic requires efficient and safe antiviral treatment strategies. Drug repurposing represents a fast and low-cost approach to the development of new medical treatment options. The direct antiviral agent remdesivir has been reported to exert antiviral activity against SARS-CoV-2. Whereas remdesivir only has a very short half-life time and a bioactivation, which relies on pro-drug activating enzymes, its plasma metabolite GS-441524 can be activated through various kinases including the adenosine kinase (ADK) that is moderately expressed in all tissues. The pharmacokinetics of GS-441524 argue for a suitable antiviral drug that can be given to patients with COVID-19. Here, we analyzed the antiviral property of a combined treatment with the remdesivir metabolite GS-441524 and the antidepressant fluoxetine in a polarized Calu-3 cell culture model against SARS-CoV-2. The combined treatment with GS-441524 and fluoxetine were well-tolerated and displayed synergistic antiviral effects against three circulating SARS-CoV-2 variants in vitro in the commonly used reference models for drug interaction. Thus, combinatory treatment with the virus-targeting GS-441524 and the host-directed drug fluoxetine might offer a suitable therapeutic treatment option for SARS-CoV-2 infections.

Highlights

Control Calu-3 cells that were treated with the solvent DMSO yielded viral titers up to 2 × 106 plaque-forming units (PFU), whereas treatment with the nucleoside GS-441524 2hpi significantly inhibited the production of the circulating SARS-CoV-2 variant in a dose-depended manner (Figure 1)
Validation of Calu-3 cell viability after administration of GS-441524 via an MTT assay revealed that only a very high were treated with the solvent DMSO yielded viral titers up to 2 × 106 PFU, whereas treatment with the nucleoside GS-441524 2hpi significantly inhibited the production of the circulating SARS-CoV-2 variant in a dose-depended manner (Figure 1)
Antiviral therapy often includes a combination of several drugs, each targeting different steps in the virus life-cycle to circumvent the emergence of drug resistance

Summary

Introduction

The Coronavirus Disease 2019 (COVID-19) caused by the Severe Acute Respiratory. Syndrome Related Coronavirus 2 (SARS-CoV-2) has resulted in over 2 million deaths within one year and demonstrates the risk of newly emerged pathogens [1,2]. In contrast to other human circulating coronaviruses, SARS-CoV-2 leads to a severe disease with multiple organ failures, especially in elderly patients and those with chronic medical conditions [3,4,5]. Their production, distribution and vaccine hesitancy are critical limiting factors in healthcare. The development and production of new antiviral drugs is a time-consuming process that can be accelerated by the repurposing of already clinically licensed drugs [6,7]

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