The SARS-COV-2 pandemic and the global spread of coronavirus disease 2019 (COVID-19) urgently calls 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 host- SARS-CoV-2 interface via repurposing of clinically licensed drugs and evaluated their use in combinatory treatments with virus- and host-directed drugs. We tested the antiviral potential of repurposing 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 remdesivir, an inhibitor of viral RNA polymerase. Drug treatments were well-tolerated and potent impaired viral replication was observed with all drug treatments. Importantly, both itraconazole-remdesivir and fluoxetine-remdesivir combinations inhibited the production of infectious SARS-CoV-2 particles > 90% and displayed synergistic effects in commonly used reference models for drug interaction. Itraconazole-Remdesivir and Fluoxetine-Remdesivir combinations are promising therapeutic options to control SARS-CoV-2 infection and severe progression of COVID-19.

中文翻译：

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瑞德昔韦与改用药物氟西汀和伊曲康唑联合治疗的药物协同作用可有效削弱SARS-CoV-2的体外感染

SARS-COV-2大流行和2019年冠状病毒疾病（COVID-19）的全球扩散迫切需要有效和安全的抗病毒治疗策略。以更低的成本加快药物开发的一种直接方法就是改变药物用途。在这里，我们研究了通过重新使用临床许可的药物来靶向宿主SARS-CoV-2接口的治疗潜力，并评估了它们在与病毒和宿主定向药物联合治疗中的用途。我们在极化的Calu-3细胞培养模型中测试了将抗真菌伊曲康唑和抗抑郁药氟西汀重新用于感染性SARS-CoV-2颗粒生产的抗病毒潜力，并评估了将这些宿主导向药物与remdesivir，病毒RNA聚合酶抑制剂。药物治疗的耐受性良好，所有药物治疗均观察到强效的病毒复制。重要的是，伊曲康唑-雷米地韦和氟西汀-雷米地韦的组合均抑制了大于90％的传染性SARS-CoV-2颗粒的产生，并在常用的药物相互作用参考模型中显示出协同作用。伊曲康唑-雷姆地西韦和氟西汀-雷姆地西韦的组合是控制SARS-CoV-2感染和COVID-19严重进展的有前途的治疗选择。