Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine

The Corona Virus Disease 2019 (COVID-19) pandemic caused by the Severe Acute Respiratory Syndrome Related Coronavirus 2 (SARS-CoV-2) is a global health emergency. As only very limited therapeutic options are clinically available, there is an urgent need for the rapid development of safe, effective,...

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Published in:bioRxiv 2020-08
Main Authors: Schloer, Sebastian, Brunotte, Linda, Goretzko, Jonas, Mecate-Zambrano, Angeles, Korthals, Nadja, Gerke, Volker, Ludwig, Stephan, Rescher, Ursula
Format: Article
Language:English
Subjects:
Acidification
Antiviral agents
Cell culture
Cholesterol
Coronaviruses
COVID-19
Cytotoxicity
Endosomes
Fluoxetine
Homeostasis
Influenza A
Pandemics
Propagation
Severe acute respiratory syndrome coronavirus 2
Sphingomyelin phosphodiesterase
Therapeutic applications
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Summary:The Corona Virus Disease 2019 (COVID-19) pandemic caused by the Severe Acute Respiratory Syndrome Related Coronavirus 2 (SARS-CoV-2) is a global health emergency. As only very limited therapeutic options are clinically available, there is an urgent need for the rapid development of safe, effective, and globally available pharmaceuticals that inhibit SARS-CoV-2 entry and ameliorate COVID-19. In this study, we explored the use of small compounds acting on the homeostasis of the endolysosomal host-pathogen interface, to fight SARS-CoV-2 infection. We find that fluoxetine, a widely used antidepressant and a functional inhibitor of acid sphingomyelinase (FIASMA), efficiently inhibited the entry and propagation of SARS-CoV-2 in the cell culture model without cytotoxic effects and also exerted potent antiviral activity against two currently circulating influenza A virus subtypes, an effect which was also observed upon treatment with the FIASMAs amiodarone and imipramine. Mechanistically, fluoxetine induced both impaired endolysosomal acidification and the accumulation of cholesterol within the endosomes. As the FIASMA group consists of a large number of small compounds that are well-tolerated and widely used for a broad range of clinical applications, exploring these licensed pharmaceuticals may offer a variety of promising antivirals for host-directed therapy to counteract enveloped viruses, including SARS-CoV-2 and COVID 19. Competing Interest Statement The authors have declared no competing interest. Footnotes * Figure 1 added, contains additional data on the antiviral activity of fluoxetine against influenza H1N1 and H3N2 strains. Figure 3 added, contains data showing the antiviral activities of additional FIASMAs against IAV stains and SARS-CoV-2.
DOI:10.1101/2020.07.27.222836