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Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine
by
Mecate-Zambrano, Angeles
, Schloer, Sebastian
, Gerke, Volker
, Goretzko, Jonas
, Brunotte, Linda
, Ludwig, Stephan
, Rescher, Ursula
, Korthals, Nadia
in
Antidepressants
/ Antidepressive Agents - pharmacology
/ Antiviral Agents - pharmacology
/ Antiviral drugs
/ Betacoronavirus - drug effects
/ Betacoronavirus - physiology
/ Cell Line
/ Coronavirus Infections - virology
/ Coronaviruses
/ COVID-19
/ endolysosomal interference
/ Endosomes - virology
/ Enzyme Inhibitors - pharmacology
/ FIASMA
/ fluoxetine
/ Fluoxetine - pharmacology
/ Humans
/ IAV
/ Pandemics
/ Pneumonia, Viral - virology
/ SARS-CoV-2
/ Severe acute respiratory syndrome coronavirus 2
/ Sphingomyelin Phosphodiesterase - antagonists & inhibitors
/ viral entry
/ Virus Replication - drug effects
2020
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Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine
by
Mecate-Zambrano, Angeles
, Schloer, Sebastian
, Gerke, Volker
, Goretzko, Jonas
, Brunotte, Linda
, Ludwig, Stephan
, Rescher, Ursula
, Korthals, Nadia
in
Antidepressants
/ Antidepressive Agents - pharmacology
/ Antiviral Agents - pharmacology
/ Antiviral drugs
/ Betacoronavirus - drug effects
/ Betacoronavirus - physiology
/ Cell Line
/ Coronavirus Infections - virology
/ Coronaviruses
/ COVID-19
/ endolysosomal interference
/ Endosomes - virology
/ Enzyme Inhibitors - pharmacology
/ FIASMA
/ fluoxetine
/ Fluoxetine - pharmacology
/ Humans
/ IAV
/ Pandemics
/ Pneumonia, Viral - virology
/ SARS-CoV-2
/ Severe acute respiratory syndrome coronavirus 2
/ Sphingomyelin Phosphodiesterase - antagonists & inhibitors
/ viral entry
/ Virus Replication - drug effects
2020
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Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine
by
Mecate-Zambrano, Angeles
, Schloer, Sebastian
, Gerke, Volker
, Goretzko, Jonas
, Brunotte, Linda
, Ludwig, Stephan
, Rescher, Ursula
, Korthals, Nadia
in
Antidepressants
/ Antidepressive Agents - pharmacology
/ Antiviral Agents - pharmacology
/ Antiviral drugs
/ Betacoronavirus - drug effects
/ Betacoronavirus - physiology
/ Cell Line
/ Coronavirus Infections - virology
/ Coronaviruses
/ COVID-19
/ endolysosomal interference
/ Endosomes - virology
/ Enzyme Inhibitors - pharmacology
/ FIASMA
/ fluoxetine
/ Fluoxetine - pharmacology
/ Humans
/ IAV
/ Pandemics
/ Pneumonia, Viral - virology
/ SARS-CoV-2
/ Severe acute respiratory syndrome coronavirus 2
/ Sphingomyelin Phosphodiesterase - antagonists & inhibitors
/ viral entry
/ Virus Replication - drug effects
2020
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Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine
Journal Article
Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine
2020
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Overview
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.
Publisher
Taylor & Francis,Taylor & Francis Ltd,Taylor & Francis Group
Subject
/ Antidepressive Agents - pharmacology
/ Antiviral Agents - pharmacology
/ Betacoronavirus - drug effects
/ Betacoronavirus - physiology
/ Coronavirus Infections - virology
/ COVID-19
/ Enzyme Inhibitors - pharmacology
/ FIASMA
/ Humans
/ IAV
/ Severe acute respiratory syndrome coronavirus 2
/ Sphingomyelin Phosphodiesterase - antagonists & inhibitors
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