Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine

Abstract

The Corona Virus 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. 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 inhibits the entry and propagation of SARS-CoV-2 in the cell culture model without cytotoxic effects. 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 SARS-CoV-2 and COVID 19.SignificanceOnly very limited therapeutic options are clinically available for treatment of Corona Virus Disease 2019 (COVID-19) pandemic caused by the Severe Acute Respiratory Syndrome Related Coronavirus 2 (SARS-CoV-2), and the development of safe, effective, and globally available pharmaceuticals are urgently required. We report that the widely used antidepressant fluoxetine efficiently inhibits the early entry and propagation of SARS-CoV-2 in the cell culture model, and may offer a promising approach for host-directed therapy to counteract SARS-CoV-2 and COVID 19.

The acid sphingomyelinase/ceramide system in COVID-19

“…In summary, our data suggest the use of FIASMA medications such as fluoxetine, amitriptyline, ambroxol, anti-ceramide antibodies and neutral ceramidase for the prevention and treatment of coronavirus disease. These data were confirmed by an independent study also following the ASM/ceramide approach that demonstrated an inhibition of the infection of cultured epithelial cells with SARS-CoV-2 by the FIASMAs fluoxetine, amiodarone and imipramine in Calu-3 and Vero E6 cells [59]. As mechanisms, the authors describe a lack of acidification in acidic organelles and a change in cholesterol abundance.…”

Keep Your Friends Close, but Your Enemies Closer: Role of Acid Sphingomyelinase During Infection and Host Response

“…It is of major interest that fluoxetine, a widely used antidepressant drug, 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 (178).…”

Repurposing Selective Serotonin Reuptake Inhibitors for COVID-19: Rationale and Concerns

“…1,2,4,8 The unconventional responsibilities, demanding working conditions, and the ambiguity in the role of the police may result in job stress and burnout and have been established in earlier studies as a source of occupational stress among Indian police personnel. 9,10 The concern about being infected from the community and workplace may also be a potential source of fear among police personnel. 1 Furthermore, concerns about carrying the infection to the family members may also be a source of psychological distress.…”