tetano
Editor, Senior Moderator
Emerg Microbes Infect
. 2020 Sep 25;1-26.
doi: 10.1080/22221751.2020.1829082. Online ahead of print.
Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine
Sebastian Schloer[SUP] 1 2 [/SUP], Linda Brunotte[SUP] 3 2 [/SUP], Jonas Goretzko[SUP] 1 2 [/SUP], Angeles Mecate-Zambrano[SUP] 3 2 [/SUP], Nadia Korthals[SUP] 1 [/SUP], Volker Gerke[SUP] 1 2 [/SUP], Stephan Ludwig[SUP] 3 2 [/SUP], Ursula Rescher[SUP] 1 2 [/SUP]
Affiliations
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 and COVID 19.
Keywords: FIASMA; IAV; SARS-CoV-2; endolysosomal interference; fluoxetine; viral entry.
. 2020 Sep 25;1-26.
doi: 10.1080/22221751.2020.1829082. Online ahead of print.
Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine
Sebastian Schloer[SUP] 1 2 [/SUP], Linda Brunotte[SUP] 3 2 [/SUP], Jonas Goretzko[SUP] 1 2 [/SUP], Angeles Mecate-Zambrano[SUP] 3 2 [/SUP], Nadia Korthals[SUP] 1 [/SUP], Volker Gerke[SUP] 1 2 [/SUP], Stephan Ludwig[SUP] 3 2 [/SUP], Ursula Rescher[SUP] 1 2 [/SUP]
Affiliations
- PMID: 32975484
- 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 and COVID 19.
Keywords: FIASMA; IAV; SARS-CoV-2; endolysosomal interference; fluoxetine; viral entry.