Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine
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, effe...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2020-01-01
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| Series: | Emerging Microbes and Infections |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/22221751.2020.1829082 |
| _version_ | 1797265894087327744 |
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| author | Sebastian Schloer Linda Brunotte Jonas Goretzko Angeles Mecate-Zambrano Nadia Korthals Volker Gerke Stephan Ludwig Ursula Rescher |
| author_facet | Sebastian Schloer Linda Brunotte Jonas Goretzko Angeles Mecate-Zambrano Nadia Korthals Volker Gerke Stephan Ludwig Ursula Rescher |
| author_sort | Sebastian Schloer |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T17:24:21Z |
| format | Article |
| id | doaj.art-bcf82b4bf73a42dcb504646c60eb279b |
| institution | Directory Open Access Journal |
| issn | 2222-1751 |
| language | English |
| last_indexed | 2024-04-25T00:52:02Z |
| publishDate | 2020-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Emerging Microbes and Infections |
| spelling | doaj.art-bcf82b4bf73a42dcb504646c60eb279b2024-03-11T16:04:24ZengTaylor & Francis GroupEmerging Microbes and Infections2222-17512020-01-01912245225510.1080/22221751.2020.1829082Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetineSebastian Schloer0Linda Brunotte1Jonas Goretzko2Angeles Mecate-Zambrano3Nadia Korthals4Volker Gerke5Stephan Ludwig6Ursula Rescher7Institute of Medical Biochemistry, Center for Molecular Biology of Inflammation, and “Cells in Motion” Interfaculty Centre, University of Muenster, Muenster, GermanyInstitute of Virology, Center for Molecular Biology of Inflammation, and “Cells in Motion” Interfaculty Centre, University of Muenster, Muenster, GermanyInstitute of Medical Biochemistry, Center for Molecular Biology of Inflammation, and “Cells in Motion” Interfaculty Centre, University of Muenster, Muenster, GermanyInstitute of Virology, Center for Molecular Biology of Inflammation, and “Cells in Motion” Interfaculty Centre, University of Muenster, Muenster, GermanyInstitute of Medical Biochemistry, Center for Molecular Biology of Inflammation, and “Cells in Motion” Interfaculty Centre, University of Muenster, Muenster, GermanyInstitute of Medical Biochemistry, Center for Molecular Biology of Inflammation, and “Cells in Motion” Interfaculty Centre, University of Muenster, Muenster, GermanyInstitute of Virology, Center for Molecular Biology of Inflammation, and “Cells in Motion” Interfaculty Centre, University of Muenster, Muenster, GermanyInstitute of Medical Biochemistry, Center for Molecular Biology of Inflammation, and “Cells in Motion” Interfaculty Centre, University of Muenster, Muenster, GermanyABSTRACTThe 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.https://www.tandfonline.com/doi/10.1080/22221751.2020.1829082SARS-CoV-2IAVFIASMAfluoxetineviral entryendolysosomal interference |
| spellingShingle | Sebastian Schloer Linda Brunotte Jonas Goretzko Angeles Mecate-Zambrano Nadia Korthals Volker Gerke Stephan Ludwig Ursula Rescher Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine Emerging Microbes and Infections SARS-CoV-2 IAV FIASMA fluoxetine viral entry endolysosomal interference |
| title | Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine |
| title_full | Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine |
| title_fullStr | Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine |
| title_full_unstemmed | Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine |
| title_short | Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine |
| title_sort | targeting the endolysosomal host sars cov 2 interface by clinically licensed functional inhibitors of acid sphingomyelinase fiasma including the antidepressant fluoxetine |
| topic | SARS-CoV-2 IAV FIASMA fluoxetine viral entry endolysosomal interference |
| url | https://www.tandfonline.com/doi/10.1080/22221751.2020.1829082 |
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