Fluoxetine Can Inhibit SARS-CoV-2 In Vitro

Dechaumes, Arthur; Nekoua, Magloire Pandoua; Belouzard, Sandrine; Sané, Famara; Engelmann, Ilka; Dubuisson, Jean; Alidjinou, Enagnon Kazali; Hober, Didier

doi:10.3390/microorganisms9020339

Cited by 38 publications

(44 citation statements)

References 42 publications

(52 reference statements)

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“…As mechanisms, the authors describe a lack of acidification in acidic organelles and a change in cholesterol abundance. The observation of the antiviral activity of fluoxetine was also confirmed in other preclinical studies [ 60 , 61 ]. Taken together, these results show the potentially crucial importance of the ASM/ceramide system as a treatment target in COVID-19, a mechanism likely to be shared by all virus variants [ 62 ].…”

Section: The Asm/ceramide System and Sars-cov-2supporting

confidence: 73%

The acid sphingomyelinase/ceramide system in COVID-19

2021

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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.

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Section: The Asm/ceramide System and Sars-cov-2supporting

confidence: 73%

The acid sphingomyelinase/ceramide system in COVID-19

2021

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“…In addition, several repurposed drugs have been introduced which are able to prevent viral entry via different mechanisms. These repurposed drugs, including fluoxetine and itraconazole, which can dysregulate the endosomal cholesterol release and increase endolysosomal cholesterol storage have been suggested as synergistic combinatory therapeutic agents alongside with conventional antiviral therapies (Creeden et al, 2021;Dechaumes et al, 2021;Schloer et al, 2021). According to these promising results, using repurposed therapeutic agents as adjuvant therapy alongside with the two-step strategy seems to be very helpful with comprehensive blockade of viral entry.…”

Section: Discussion and Future Directionmentioning

confidence: 99%

“…Schloer et al (2020) and Zimniak et al (2021) showed the efficacy of these host-directed drugs in fighting COVID-19 infection both alone and in combination with an antiviral drug, remdesivir. In another study, they investigated the in vitro antiviral activity of fluoxetine against SARS-CoV-2 in a model of acute infection and the level of infectious particles was lower than that in controls (Dechaumes et al, 2021). The mechanism through which fluoxetine exhibits its inhibitory effect in viral cell entry is that it prevents endolysosomal acidification by inactivating endolysosomal proton pump (v-ATPase) which leads to endolysosomal pH neutralization.…”

Section: Supporting Evidences For Strategy Cell Entry Mechanism Of Sars-cov-2mentioning

confidence: 99%

Developing Cytokine Storm-Sensitive Therapeutic Strategy in COVID-19 Using 8P9R Chimeric Peptide and Soluble ACE2

Nazerian

Vakili

Ebrahimi

et al. 2021

Front. Cell Dev. Biol.

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Currently, the COVID-19 pandemic is an international challenge, largely due to lack of effective therapies. Pharmacotherapy has not yet been able to find a definitive treatment for COVID-19. Since SARS-CoV-2 affects several organs, treatment strategies that target the virus in a wider range are expected to be ultimately more successful. To this end, a two-step treatment strategy has been presented. In the first phase of the disease, when the patient is newly infected with the virus and the cytokine storm has not yet been developed, a chimeric peptide is used to inhibit virus entry into the host cell cytosol (by inhibiting endosomal pH acidification) and viral replication. After the virus entry and decrease of angiotensin converting enzyme 2 (ACE2) level, some people are unable to properly compensate for the ACE2 pathway and progress toward the cytokine storm. In the beginning of the cytokine storm, sACE2 protein is very effective in regulating the immune system toward the anti-inflammatory pathway, including M2 macrophages. Hence, the genes of 8P9R chimeric peptide and sACE2 would be inserted in an episomal vector with a separate promoter for each gene: the chimeric peptide gene promoter is a CMV promoter, while the sACE2 gene promoter is a NF-κB-sensitive promoter. The NF-κB-sensitive promoter induces the expression of sACE2 gene soon after elevation of NF-κB which is the main transcription factor of inflammatory genes. Thus, as the expression of inflammatory cytokines increases, the expression of sACE2 increases simultaneously. In this condition, sACE2 can prevent the cytokine storm by inhibiting the pro-inflammatory pathways. To deliver the designed vector to the target cells, mesenchymal stem cell-derived (MSC-derived) exosome-liposome hybrids are used. Herein, the strategy can be considered as a personalized clinical therapy for COVID-19, that can prevent morbidity and mortality in the future.

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“…The HEp-2 cell line (BioWhittaker, Verviers, Belgium) was cultured in Eagle’s Minimum Essential Medium supplemented with 10% FCS, 100 U/mL penicillin and 100 μg/mL streptomycin, and 1% L-glutamine. The diabetogenic strain CV-B4 E2 was provided by Ji-Won Yoon (Julia McFarlane Diabetes Research Center, Calgary, AB, Canada) and was propagated in HEp-2 cells as previously described [ 33 , 36 ]. The viral titers in supernatants were assessed on HEp-2 cell monolayers using the end-point dilution assay.…”

Section: Methodsmentioning

confidence: 99%

Persistence of Coxsackievirus B4 in Pancreatic β Cells Disturbs Insulin Maturation, Pattern of Cellular Proteins, and DNA Methylation

et al. 2021

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Coxsackievirus-B4 (CV-B4) can persist in pancreatic cell lines and impair the phenoytpe and/or gene expressions in these cells; however, the models used to study this phenomenon did not produce insulin. Therefore, we investigated CV-B4 persistence and its consequences in insulin-producing pancreatic β cells. The insulin-secreting rat β cell line, INS-1, was infected with CV-B4. After lysis of a large part of the cell layer, the culture was still maintained and no additional cytopathic effect was observed. The amount of insulin in supernatants of cell cultures persistently infected with CV-B4 was not affected by the infection; in fact, a larger quantity of proinsulin was found. The mRNA expression of pro-hormone convertase 2, an enzyme involved in the maturation of proinsulin into insulin and studied using real-time reverse transcription-polymerase chain reaction, was inhibited in infected cultures. Further, the pattern of 47 cell proteins analyzed using Shotgun mass spectrometry was significantly modified. The DNA of persistently infected cell cultures was hypermethylated unlike that of controls. The persistent infection of INS-1 cells with CV-B4 had a deep impact on these cells, especially on insulin metabolism. Cellular changes caused by persistent CV-B4 infection of β cells can play a role in type 1 diabetes pathogenesis.

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Fluoxetine Can Inhibit SARS-CoV-2 In Vitro

Cited by 38 publications

References 42 publications

The acid sphingomyelinase/ceramide system in COVID-19

The acid sphingomyelinase/ceramide system in COVID-19

Developing Cytokine Storm-Sensitive Therapeutic Strategy in COVID-19 Using 8P9R Chimeric Peptide and Soluble ACE2

Persistence of Coxsackievirus B4 in Pancreatic β Cells Disturbs Insulin Maturation, Pattern of Cellular Proteins, and DNA Methylation

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