Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine
| Title: | Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine |
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| Authors: | Sebastian Schloer, Linda Brunotte, Jonas Goretzko, Angeles Mecate-Zambrano, Nadia Korthals, Volker Gerke, Stephan Ludwig, Ursula Rescher |
| Source: | Emerging Microbes and Infections, Vol 9, Iss 1, Pp 2245-2255 (2020) |
| Publisher Information: | Taylor & Francis Group, 2020. |
| Publication Year: | 2020 |
| Collection: | LCC:Infectious and parasitic diseases LCC:Microbiology |
| Subject Terms: | SARS-CoV-2, IAV, FIASMA, fluoxetine, viral entry, endolysosomal interference, Infectious and parasitic diseases, RC109-216, Microbiology, QR1-502 |
| More Details: | ABSTRACTThe 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 22221751 2222-1751 |
| Relation: | https://doaj.org/toc/2222-1751 |
| DOI: | 10.1080/22221751.2020.1829082 |
| Access URL: | https://doaj.org/article/bcf82b4bf73a42dcb504646c60eb279b |
| Accession Number: | edsdoj.bcf82b4bf73a42dcb504646c60eb279b |
| Database: | Directory of Open Access Journals |
| ISSN: | 22221751 |
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| DOI: | 10.1080/22221751.2020.1829082 |
| Published in: | Emerging Microbes and Infections |
| Language: | English |