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

Emerg Microbes Infect. 2020 Dec;9(1):2245-2255. doi: 10.1080/22221751.2020.1829082.

Abstract

The Coronavirus 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 severity. 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.

Keywords: FIASMA; IAV; SARS-CoV-2; endolysosomal interference; fluoxetine; viral entry.

MeSH terms

  • Antidepressive Agents / pharmacology*
  • Antiviral Agents / pharmacology*
  • Betacoronavirus / drug effects*
  • Betacoronavirus / physiology
  • COVID-19
  • Cell Line
  • Coronavirus Infections / virology*
  • Endosomes / virology
  • Enzyme Inhibitors / pharmacology*
  • Fluoxetine / pharmacology*
  • Humans
  • Pandemics
  • Pneumonia, Viral / virology*
  • SARS-CoV-2
  • Sphingomyelin Phosphodiesterase / antagonists & inhibitors
  • Virus Replication / drug effects

Substances

  • Antidepressive Agents
  • Antiviral Agents
  • Enzyme Inhibitors
  • Fluoxetine
  • Sphingomyelin Phosphodiesterase

Grant support

This research was funded by grants from German Research Foundation (DFG), CRC1009 “Breaking Barriers,” Project A06 (to U.R.) and B02 (to S.L.), CRC1348 “Dynamic Cellular Interfaces,” Project A11 (to U.R.), KFO342 TP6, Br5189/3-1 (to L.B.), Lu477/30-1 (to S.L.), Interdisciplinary Center for Clinical Research (IZKF) of the Münster Medical School [grant number Re2/022/20] and from the Innovative Medizinische Forschung (IMF) of the Münster Medical School [grant number SC121912] (to S.S.).