Repurposing functional inhibitors of acid sphingomyelinase (fiasmas): an opportunity against SARS-CoV-2 infection?

Abstract

What is known and objective: Infection by SARS-CoV-2, the virus responsible of COVID-19, is associated with limited treatment options. The purpose of this study was to evaluate the rationale for repurposing functional inhibitors of acid sphingomyelinase (FIASMAs), several of which are approved medicines, for the treatment of SAR-CoV-2 infections.

Comment: We propose and discuss the FIASMAs' lysosomotropism as a possible explanation for their observed in vitro activities against viruses, and more specifically against infections caused by coronaviruses such as SARS-CoV-2. Successful in vitro-to-in vivo translation of FIASMAs requires that their pharmacokinetics (dosing regimen and drug-drug interactions) are matched with viral kinetics.

What is new and conclusion: Drug repurposing to ensure rapid patient access to effective treatment has garnered much attention in this era of the COVID-19 pandemic. The observed lysosomotropic activity of small-molecule FIASMA compounds suggests that their repurposing as potential drugs against SARS-CoV-2 is promising.

Keywords: ABCB1 transporter; SARS-CoV-2; acid sphingomyelinase; antiviral activity; functional inhibitors of acid sphingomyelinase; in vitro and in silico; repurposing.

FIGURE 1

Mechanisms of action of functional inhibitors of acid sphingomyelinase (ASM). Left: ASM is anchored to the inner leaflet of the lysosomal membrane by electrostatic forces so that the enzyme is protected from proteolytic degradation. Specific stimuli allow the translocation of ASM from the inner lysosome to the external leaflet of the cell where ASM catalyses the hydrolysis of sphingomyelin into ceramide and phosphorylcholine. Sphingomyelin is the most abundant sphingolipid component of the mammalian plasma membrane where it is associated with cholesterol to form lipid rafts. Right: FIASMA are cationic drugs with lipophilic properties that diffuse in the lysosome by passive diffusion and potentially via an additional mechanism using ABCB1 transporter located on the lysosomal membrane. These drugs become protonated in the intra‐lysosomal acidic environment and increase the intra‐lysosomal pH so that ASM is detached from the inner leaflet of the lysosomal membrane and is further degraded by proteolysis. ASM translocation is no longer effective and the formation of lipid rafts is altered. Hence, different mechanisms of internalization used by viruses (ie fusion and entry) to penetrate in the cytosol of cells are altered.