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.

Update on Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) in SARS-CoV-2 Infection

“…In 2020, among the 23 in silico, in vitro or ex vivo studies reporting activity of FIASMAs against SARS-CoV-2 [ 4 ], only two cited the inhibition of ASM as the principal mechanism of action of the drugs [ 3 , 12 ].…”

“…Recently (9 January 2021), we reviewed [ 4 ] all the corresponding studies (N = 27), including the pre-print publications, and found that thirty-two FIASMAs could be considered as potential drugs for treating SARS-CoV-2.…”

Ceramide and Related Molecules in Viral Infections

“…Future work should focus on further defining the involvement of sphingolipids in viral entry, replication and release with the hope of identifying new antiviral therapeutic targets. Of particular current interest in light of the SARS-CoV-2/COVID-19 pandemic is the repurposing of FIASMAs for the inhibition of SARS-CoV-2 entry [ 83 , 84 , 88 , 89 , 90 , 91 , 92 , 93 ]. The long-standing clinical experience with these drugs and their favorable pharmacological properties, including good absorption, distribution, metabolism and excretion, lack of habituation, reversible inhibition and lack of rebound effects [ 229 ] make them ideal candidates for a swift indication expansion to manage SARS-COV-2 infection/COVID-19.…”

Low-dose fluvoxamine modulates endocytic trafficking of SARS-CoV-2 spike protein: a potential mechanism for anti-COVID-19 protection by antidepressants

“…Foremost amongst these is a generic selective serotonin reuptake inhibitor (SSRI) fluvoxamine, that has been shown to protect against severe COVID-19 in a Phase 2 trial 8 as well as a real-world study 9 and is currently undergoing a Phase 3 study 10 . The suggested protective effect of fluvoxamine has been tentatively linked to modulation of immune response through activation of the ER stress and sigma receptor 11 , or blockade of acid sphingomyelinase 7,12,13 , however the underlying cell biological mechanism remains unknown.…”

“…Foremost amongst these is a generic selective serotonin reuptake inhibitor (SSRI) fluvoxamine, that has been shown to protect against severe COVID-19 in a Phase 2 trial 8 as well as a real-world study 9 and is currently undergoing a Phase 3 study 10 . The suggested protective effect of fluvoxamine has been tentatively linked to modulation of immune response through activation of the ER stress and sigma receptor 11 , or blockade of acid sphingomyelinase 7,12,13 , however the underlying cell biological mechanism remains unknown.It had been suggested that pharmacological modulation of SARS-CoV-2 membrane trafficking might offer a strategy for both treatment and prophylaxis of COVID-19, and a list of candidate drugs included fluvoxamine 14 . Given the emergence of clinical data suggesting efficacy of fluvoxamine against COVID-19, the effect of fluvoxamine treatment on membrane 1 .…”