The Acid Ceramidase Is a SARS-CoV-2 Host Factor

SARS-CoV-2 variants such as the delta or omicron variants, with higher transmission rates, accelerated the global COVID-19 pandemic. Thus, novel therapeutic strategies need to be deployed. The inhibition of acid sphingomyelinase (ASM), interfering with viral entry by fluoxetine was reported. Here, w...

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Veröffentlicht in:Cells (Basel, Switzerland) Jg. 11; H. 16; S. 2532
Hauptverfasser: Geiger, Nina, Kersting, Louise, Schlegel, Jan, Stelz, Linda, Fähr, Sofie, Diesendorf, Viktoria, Roll, Valeria, Sostmann, Marie, König, Eva-Maria, Reinhard, Sebastian, Brenner, Daniela, Schneider-Schaulies, Sibylle, Sauer, Markus, Seibel, Jürgen, Bodem, Jochen
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Basel MDPI AG 01.08.2022
MDPI
Schlagworte:
acid sphingomyelinase
Cell culture
Ceramidase
Ceramide
ceramides
Chromatography
Coronaviruses
COVID-19
Enzymes
Fluoxetine
Gene expression
Genomes
Health aspects
Immunization
Infections
Mortality
pH effects
Replication
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
Sphingomyelin phosphodiesterase
Supplements
Vaccines
Viruses
Germany
United States > US
ISSN:2073-4409, 2073-4409
Online-Zugang:Volltext
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Zusammenfassung:SARS-CoV-2 variants such as the delta or omicron variants, with higher transmission rates, accelerated the global COVID-19 pandemic. Thus, novel therapeutic strategies need to be deployed. The inhibition of acid sphingomyelinase (ASM), interfering with viral entry by fluoxetine was reported. Here, we described the acid ceramidase as an additional target of fluoxetine. To discover these effects, we synthesized an ASM-independent fluoxetine derivative, AKS466. High-resolution SARS-CoV-2–RNA FISH and RTqPCR analyses demonstrate that AKS466 down-regulates viral gene expression. It is shown that SARS-CoV-2 deacidifies the lysosomal pH using the ORF3 protein. However, treatment with AKS488 or fluoxetine lowers the lysosomal pH. Our biochemical results show that AKS466 localizes to the endo-lysosomal replication compartments of infected cells, and demonstrate the enrichment of the viral genomic, minus-stranded RNA and mRNAs there. Both fluoxetine and AKS466 inhibit the acid ceramidase activity, cause endo-lysosomal ceramide elevation, and interfere with viral replication. Furthermore, Ceranib-2, a specific acid ceramidase inhibitor, reduces SARS-CoV-2 replication and, most importantly, the exogenous supplementation of C6-ceramide interferes with viral replication. These results support the hypotheses that the acid ceramidase is a SARS-CoV-2 host factor.
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Current Address: Department of Women’s and Children’s Health, Karolinska Institutet, SciLifeLab, Tomtebodavägen 23B, Solna, 171 65 Stockholm, Sweden.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells11162532