FIASMA

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.

Abstract: Acid sphingomyelinase (ASM) cleaves sphingomyelin into the highly lipophilic ceramide, which forms large gel-like rafts/platforms in the plasma membrane. We showed that SARS-CoV-2 uses these platforms for cell entry. Lowering the amount of ceramide or ceramide blockade due to inhibitors of ASM, genetic downregulation of ASM, anti-ceramide antibodies or degradation by neutral ceramidase protected against infection with SARS-CoV-2. The addition of ceramide restored infection with SARS-CoV-2. Many clinically approved medications functionally inhibit ASM and are called FIASMAs (functional inhibitors of acid sphingomyelinase). The FIASMA fluvoxamine showed beneficial effects on COVID-19 in a randomized prospective study and a prospective open-label real-world study. Retrospective and observational studies showed favorable effects of FIASMA antidepressants including fluoxetine, and the FIASMA hydroxyzine on the course of COVID-19. The ASM/ceramide system provides a framework for a better understanding of the infection of cells by SARS-CoV-2 and the clinical, antiviral, and anti-inflammatory effects of functional inhibitors of ASM. This framework also supports the development of new drugs or the repurposing of “old” drugs against COVID-19.

Abstract: Breakdown of the inert and constitutive membrane building block sphingomyelin to the highly active lipid mediator ceramide by extracellularly active acid sphingomyelinase is tightly regulated during stress response and opens the gate for invading pathogens, triggering the immune response, development of remote organ failure, and tissue repair following severe infection. How do one enzyme and one mediator manage all of these affairs? Under physiological conditions, the enzyme is located in the lysosomes and takes part in the noiseless metabolism of sphingolipids, but following stress the protein is secreted into circulation. When secreted, acid sphingomyelinase (ASM) is able to hydrolyze sphingomyelin present at the outer leaflet of membranes to ceramide. Its generation troubles the biophysical context of cellular membranes resulting in functional assembly and reorganization of proteins and receptors, also embedded in highly conserved response mechanisms. As a consequence of cellular signaling, not only induction of cell death but also proliferation, differentiation, and fibrogenesis are affected. Here, we discuss the current state of the art on both the impact and function of the enzyme during host response and damage control. Also, the potential role of lysosomotropic agents as functional inhibitors of this upstream alarming cascade is highlighted.