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

Sebastian Schloer, Linda Brunotte, Angeles Mecate-Zambrano, Shuyu Zheng, Jing Tang, Stephan Ludwig, View ORCID ProfileUrsula Rescher
doi: https://doi.org/10.1101/2020.10.16.342410
Sebastian Schloer
1Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, and “Cells in Motion” Interfaculty Centre, University of Muenster, Von-Esmarch-Str. 56, D-48149, Muenster, Germany
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Linda Brunotte
2Institute of Molecular Virology, Center for Molecular Biology of Inflammation, and “Cells in Motion” Interfaculty Centre, University of Muenster, Von-Esmarch-Str. 56, D-48149, Muenster, Germany
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Angeles Mecate-Zambrano
2Institute of Molecular Virology, Center for Molecular Biology of Inflammation, and “Cells in Motion” Interfaculty Centre, University of Muenster, Von-Esmarch-Str. 56, D-48149, Muenster, Germany
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Shuyu Zheng
3Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, 00029, Helsinki, Finland
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Jing Tang
3Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, 00029, Helsinki, Finland
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Stephan Ludwig
2Institute of Molecular Virology, Center for Molecular Biology of Inflammation, and “Cells in Motion” Interfaculty Centre, University of Muenster, Von-Esmarch-Str. 56, D-48149, Muenster, Germany
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Ursula Rescher
1Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, and “Cells in Motion” Interfaculty Centre, University of Muenster, Von-Esmarch-Str. 56, D-48149, Muenster, Germany
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  • ORCID record for Ursula Rescher
  • For correspondence: rescher@uni-muenster.de
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ABSTRACT

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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 16, 2020.
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Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS-CoV-2 infection in vitro
Sebastian Schloer, Linda Brunotte, Angeles Mecate-Zambrano, Shuyu Zheng, Jing Tang, Stephan Ludwig, Ursula Rescher
bioRxiv 2020.10.16.342410; doi: https://doi.org/10.1101/2020.10.16.342410
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Drug synergy of combinatory treatment with remdesivir and the repurposed drugs fluoxetine and itraconazole effectively impairs SARS-CoV-2 infection in vitro
Sebastian Schloer, Linda Brunotte, Angeles Mecate-Zambrano, Shuyu Zheng, Jing Tang, Stephan Ludwig, Ursula Rescher
bioRxiv 2020.10.16.342410; doi: https://doi.org/10.1101/2020.10.16.342410

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