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.
Highlights
SARS-COV-2 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is closely related to the deadly coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV)
THE ACID SPHINGOMYELINASE/CERAMIDE SYSTEM Surface ceramide is generated by the acid sphingomyelinase (ASM), which is a lysosomal protein that catalyzes the conversion of sphingomyelin into ceramide
Since lysosomes are constantly recycling to the plasma membrane, the ASM can be found on the cell surface and binds to the outer leaflet of the plasma membrane [14–16]
Summary
Acid sphingomyelinase (ASM) cleaves sphingomyelin into the highly lipophilic ceramide, which forms large gel-like rafts/platforms in the plasma membrane. This clinical evidence suggests that the beneficial effects of certain antidepressants, such as fluoxetine or fluvoxamine, and the H1 antihistamine hydroxyzine, which are FIASMAs [34], in patients with COVID-19 may be mediated by the inhibition of ASM These findings support the continuation of FIASMA medications during SARS-CoV-2 infection [80, 81]. Elevated approved FIASMAs fluoxetine or fluvoxamine, which display high ceramide levels have been associated with higher age in vitro inhibition effect on ASM, showed potential positive effects [112–116], hypertension [117] and obesity [118], three of at usual antidepressant doses, and are easy to use, including high the major risk factors for the development of severe safety margins, good tolerability, widespread availability and low infections with SARS-CoV-2 [5]. FIASMAs may prevent the thromboembolic complications of SARS-CoV-2 infection
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