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.
【저자키워드】 Diseases, Molecular biology, 【초록키워드】 COVID-19, SARS-CoV-2, Open-label, Antiviral, antibody, Prospective Study, Genetic, Infection, repurposing, drug, medications, antidepressants, inhibitors, observational studies, observational study, Randomized, fluvoxamine, Degradation, medication, inhibitor, platform, Fluoxetine, Neutral, framework, hydroxyzine, Support, ceramide, cell entry, downregulation, blockade, plasma membrane, lowering, acid, sphingomyelin, Effect, Cell, Course, addition, clinically, inhibit, form, approved, functional, provide, restored, cleave, favorable effect, infection with SARS-CoV-2, 【제목키워드】 COVID-19,