Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine.
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.
['Schloer|Sebastian|S|', 'Brunotte|Linda|L|https://orcid.org/0000-0001-8074-7400', 'Goretzko|Jonas|J|', 'Mecate-Zambrano|Angeles|A|', 'Korthals|Nadia|N|', 'Gerke|Volker|V|', 'Ludwig|Stephan|S|https://orcid.org/0000-0003-4490-3052', 'Rescher|Ursula|U|https://orcid.org/0000-0001-8892-319X']
D000928:Antidepressive Agents D000998:Antiviral Agents D000073640:Betacoronavirus D000086382:COVID-19 D002460:Cell Line D018352:Coronavirus Infections D011992:Endosomes D004791:Enzyme Inhibitors D005473:Fluoxetine D006801:Humans D058873:Pandemics D011024:Pneumonia, Viral D000086402:SARS-CoV-2 D013108:Sphingomyelin Phosphodiesterase D014779:Virus Replication
FIASMA fluoxetine SARS-CoV-2 IAV endolysosomal interference viral entry