Acid sphingomyelinase (ASM) and COVID‐19: A review of the potential use of ASM inhibitors against SARS‐CoV‐2. (17th March 2023)

• Record Type: Journal Article
• Authors: Pauletto, Pedro José Tronco; Delgado, Cassia Pereira; da Rocha, João Batista Teixeira
• Is Part Of: Cell biochemistry and function. Volume 41:Number 3(2023)
• Page Start: 284
• Page End: 295
• Publication Date: 2023-03-17
• Subjects: ASM -- FIASMAs -- lysosomal -- repurposing drugs -- SARS‐CoV‐2; Cytochemistry -- Periodicals; Cell metabolism -- Periodicals; Biochemistry -- Periodicals; Cytology -- Periodicals; 572
• DOI: 10.1002/cbf.3789
• Languages: English
• ISSNs: 0263-6484

Abstract

Abstract: In the last 2 years, different pharmacological agents have been indicated as potential inhibitors of SARS‐CoV‐2 in vitro. Specifically, drugs termed as functional inhibitors of acid sphingomyelinase (FIASMAs) have proved to inhibit the SARS‐CoV‐2 replication using different types of cells. Those therapeutic agents share several chemical structure characteristics and some well‐known representatives are fluoxetine, escitalopram, fluvoxamine, and others. Most of the FIASMAs are primarily used as effective therapeutic agents to treat different pathologies, therefore, they are natural drug candidates for repositioning strategy. In this review, we summarize the two main proposed mechanisms mediating acid sphingomyelinase (ASM) inhibition and how they can explain the inhibition of SARS‐CoV‐2 replication by FIASMAs. The first mechanism implies a disruption in the lysosomal pH fall as the endosome–lysosome moves toward the interior of the cell. In fact, changes in cholesterol levels in endosome–lysosome membranes, which are associated with ASM inhibition is thought to be mediated by lysosomal proton pump (ATP‐ase) inactivation. The second mechanism involves the formation of an extracellular ceramide‐rich domain, which is blocked by FIASMAs. The ceramide‐rich domains are believed to facilitate the SARS‐CoV‐2 entrance into the host cells. Significance statement: ASM functional inhibitors (FIASMAs) have been shown to inhibit SARS‐CoV‐2 in vitro. There are two mechanisms proposed to explain the inhibitory effects of FIASMAs against SARS‐CoV‐2. In this review, we discuss the two main hypotheses as well as the controversies about the potential efficacy of FIASMAs in COVID‐19 disease.