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

Pauletto, Pedro José Tronco; Delgado, Cássia Pereira; Rocha, João Batista Teixeira da

doi:10.1002/cbf.3789

Cited by 3 publications

(2 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In particular, analysis of data obtained in in silico, in vitro, or in vivo studies suggested the use of 49 FIASMAs in the treatment of SARS-CoV-2 infection, although outcomes from randomized double-blind clinical trials are available only for amlodipine and fluvoxamine [98]. Moreover, recent findings also suggested antidepressants involved in SL-controlled autophagy (a cellular catabolic process leading to lysosomal degradation and recycling of proteins and organelles) linked to lysosomal proton pump (ATP-ase) inactivation and block of extracellular Cer-rich domain formation [99,100].…”

Section: Sphingolipids As Potential Therapeutic Targets In Sars-cov-2...mentioning

confidence: 99%

The Sphingolipid-Signaling Pathway as a Modulator of Infection by SARS-CoV-2

Fenizia,

Gaggini,

Vassalle

2023

CIMB

View full text Add to dashboard Cite

Ceramides and other related sphingolipids, important cellular components linked to metabolic homeostasis and cardiometabolic diseases, have been found to be involved in different steps of the SARS-CoV-2 life cycle. Hence, changes in their physiological levels are identified as predictors of COVID-19 severity and prognosis, as well as potential therapeutic targets. In this review, an overview of the SARS-CoV-2 life cycle is given, followed by a description of the sphingolipid metabolism and its role in viral infection, with a particular focus on those steps required to finalize the viral life cycle. Furthermore, the use and development of pharmaceutical strategies to target sphingolipids to prevent and treat severe and long-term symptoms of infectious diseases, particularly COVID-19, are reviewed herein. Finally, research perspectives and current challenges in this research field are highlighted. Although many aspects of sphingolipid metabolism are not fully known, this review aims to highlight how the discovery and use of molecules targeting sphingolipids with reliable and selective properties may offer new therapeutic alternatives to infectious and other diseases, including COVID-19.

show abstract

Section: Sphingolipids As Potential Therapeutic Targets In Sars-cov-2...mentioning

confidence: 99%

The Sphingolipid-Signaling Pathway as a Modulator of Infection by SARS-CoV-2

Fenizia,

Gaggini,

Vassalle

2023

CIMB

View full text Add to dashboard Cite

show abstract

“…This interferes with intracellular endolyosomal viral trafficking. 17 Although many drugs are classified as FIASMAs, and some of the earlier research focussed on the closely related compound fluvoxamine, fluoxetine, which is on the WHO's list of Essential Medications, 18 was found to have the greatest in vitro FIASMA activity, the best tolerability profile, and the most favourable pharmacokinetic properties. 19 In vitro anti-SARS-CoV-2 activity has been shown at fluoxetine concentrations approximating those during the treatment of depression (20 mg daily; 0.8 µg/ml, 2.6 µM).…”

Section: Introductionmentioning

confidence: 99%

Antiviral efficacy of fluoxetine in early symptomatic COVID-19: an open-label, randomised, controlled, adaptive platform trial (PLATCOV)

Jittamala,

Boyd,

Schilling

et al. 2024

Preprint

View full text Add to dashboard Cite

Background The selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine were repurposed for the treatment of early COVID-19 based on their antiviral activity in vitro, and observational and clinical trial evidence suggesting they prevented progression to severe disease. However, these SSRIs have not been recommended in guidelines and their antiviral activity in vivo has not been characterised. Methods PLATCOV is an open-label, multicentre, phase 2, randomised, controlled, adaptive pharmacometric platform trial running in Thailand, Brazil, Pakistan, and Laos. We recruited low-risk adult outpatients aged 18-50 with early symptomatic COVID-19 (symptoms <4 days). Patients were assigned using block randomisation to one of eleven treatment arms including oral fluoxetine (40mg/day for 7 days), or no study drug. Uniform randomisation ratios were applied across the active treatment groups while the no study drug group comprised >20% of patients at all times. The primary endpoint was the rate of oropharyngeal viral clearance assessed in a modified intention-to-treat population (>2 days follow-up). The viral clearance rate was estimated under a Bayesian hierarchical linear model fitted to the log10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over one week (18 measurements per patient). This ongoing trial is registered at ClinicalTrials.gov (NCT05041907). Findings Between 5 April 2022 and 8 May 2023 271 patients were concurrently randomised to either fluoxetine (n=120) or no study drug (n=151). Fluoxetine was well tolerated and accelerated the rate of viral clearance relative to the no study drug arm by 15% (95% credible interval (CrI): 2% to 34%). In a pooled meta-analysis including all unblinded patients the antiviral activity of fluoxetine was substantially less than ritonavir-boosted nirmatrelvir- 85% increase in rate of viral clearance (95% CrI: 61 to 112%); and less than remdesivir 35% (14 to 59%), molnupiravir 37% (18 to 60%), and casirivimab/imdevimab 29% (10 to 48%). Interpretation Fluoxetine has in vivo antiviral activity against SARS-CoV-2. Although the level of antiviral efficacy is substantially less than with other currently available antiviral drugs, fluoxetine might still be useful in prophylaxis where less antiviral effect is required. Funding Wellcome Trust Grant ref: 223195/Z/21/Z through the COVID-19 Therapeutics Accelerator.

show abstract

Direct lipid interactions control SARS-CoV-2 M protein conformational dynamics and virus assembly

Dutta,

Dolan,

Amiar

et al. 2024

Preprint

View full text Add to dashboard Cite

M is the most abundant structural membrane protein in coronaviruses and is essential for the formation of infectious virus particles. SARS-CoV-2 M adopts two conformations, Mshort and Mlong, and regulated transition between states is hypothesized to coordinate viral assembly and budding. However, the factors that regulate M conformation and roles for each state are unknown. Here, we discover a direct M-sphingolipid interaction that controls M conformational dynamics and virus assembly. We show M binds Golgi-enriched anionic lipids including ceramide-1-phosphate (C1P). Molecular dynamics simulations show C1P interaction promotes a long to short transition and energetically stabilizes Mshort. Cryo-EM structures show C1P specifically binds Mshort at a conserved site bridging transmembrane and cytoplasmic regions. Disrupting Mshort-C1P interaction alters M subcellular localization, reduces interaction with Spike and E, and impairs subsequent virus-like particle cell entry. Together, these results show endogenous signaling lipids regulate M structure and support a model in which Mshort is stabilized in the early endomembrane system to organize other structural proteins prior to viral budding.

show abstract

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

Cited by 3 publications

References 86 publications

The Sphingolipid-Signaling Pathway as a Modulator of Infection by SARS-CoV-2

The Sphingolipid-Signaling Pathway as a Modulator of Infection by SARS-CoV-2

Antiviral efficacy of fluoxetine in early symptomatic COVID-19: an open-label, randomised, controlled, adaptive platform trial (PLATCOV)

Direct lipid interactions control SARS-CoV-2 M protein conformational dynamics and virus assembly

Contact Info

Product

Resources

About