TY  - JOUR
A1  - Geiger, Nina
A1  - Kersting, Louise
A1  - Schlegel, Jan
A1  - Stelz, Linda
A1  - Fähr, Sofie
A1  - Diesendorf, Viktoria
A1  - Roll, Valeria
A1  - Sostmann, Marie
A1  - König, Eva-Maria
A1  - Reinhard, Sebastian
A1  - Brenner, Daniela
A1  - Schneider-Schaulies, Sibylle
A1  - Sauer, Markus
A1  - Seibel, Jürgen
A1  - Bodem, Jochen
T1  - The acid ceramidase is a SARS-CoV-2 host factor
T2  - Cells
N2  - 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.
KW  - SARS-CoV-2
KW  - ceramides
KW  - ceramidase
KW  - fluoxetine
KW  - acid sphingomyelinase
Y1  - 2022
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/28610
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-286105
SN  - 2073-4409
VL  - 11
IS  - 16
ER  -