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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.

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.

SUBMITTER: Schloer S

PROVIDER: S-EPMC7594754 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Previous research has shown that fibroblast growth factor 2 protein (FGF2) can act as an anxiolytic and anti-depressive agent in rodents. Levels of hippocampal FGF2 and FGF2 receptors are decreased in post-mortem brains of individuals with mood disorders. No changes in FGF2 were noted in the post-mortem brains of individuals with mood disorders that were successfully treated with anti-depressant medication prior to death. Mutations in the FGF2 gene in humans have been shown to predict non-responsiveness to the therapeutic effects of selective serotonin reuptake inhibitors (SSRIs). These findings suggest that FGF2 may potentially be a target of and/or required for the therapeutic effects of antidepressant medications. To test this, we employed a rodent model of depressive behaviour, chronic variable stress (CVS) in conjunction with antidepressant treatment (fluoxetine) in wild-type (WT) and FGF2 knockout mice (FGF2KO) and examined depressive and anxiety behaviors. Results showed that fluoxetine reversed the effects of CVS on depressive and anxiety behaviours in wild-type mice only, suggesting that the FGF2 gene is indeed necessary for the therapeutic effects of fluoxetine. Interestingly, CVS decreased hippocampal FGF2 levels and fluoxetine partially reversed this effect. Because FGF2 has been previously shown to modify HPA activity through hippocampal glucocorticoid receptors (GR), we examined levels of glucocorticoid receptors and found a decrease in GR in response to CVS, with a further decrease in FGF2KO. No effect of fluoxetine on GR was observed in either WT or FGF2KO mice. This suggests that further changes in glucocorticoid receptors are not necessary for the anti-depressant effects of fluoxetine in WT mice, although decreased glucocorticoid receptors in response to FGF2 deletion may preclude the therapeutic actions of fluoxetine in FGF2KO. Whether astroglia, astroglial functions, or HPA changes are the downstream target of FGF2-mediated changes induced by fluoxetine remains to be determined, however, the current study reaffirms the potential of FGF2 as a novel therapeutic target in the treatment of depression and anxiety disorders.

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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.

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