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Updated: Aug 30, 2025

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

Nina Geiger1, Louise Kersting2, Jan Schlegel3

  • 1Institute of Virology und Immunobiology, Julius-Maximilians-Universität Würzburg, Versbacher Str. 7, 97078 Würzburg, Germany.

Cells
|August 26, 2022
PubMed
Summary

Fluoxetine and its derivative AKS466 target acid ceramidase, inhibiting SARS-CoV-2 replication by altering lysosomal pH and ceramide levels. This reveals acid ceramidase as a crucial host factor for viral proliferation.

Keywords:
SARS-CoV-2acid sphingomyelinaseceramidaseceramidesfluoxetine

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Area of Science:

  • Virology
  • Biochemistry
  • Drug Discovery

Background:

  • SARS-CoV-2 variants necessitate new therapeutic strategies.
  • Fluoxetine was previously shown to inhibit viral entry by targeting acid sphingomyelinase (ASM).
  • The role of acid ceramidase in SARS-CoV-2 infection was unexplored.

Purpose of the Study:

  • To identify acid ceramidase as a novel target of fluoxetine.
  • To investigate the mechanism by which fluoxetine and its derivative AKS466 inhibit SARS-CoV-2 replication.
  • To explore the potential of targeting acid ceramidase for COVID-19 treatment.

Main Methods:

  • Synthesis of an ASM-independent fluoxetine derivative (AKS466).
  • High-resolution SARS-CoV-2-RNA Fluorescence In Situ Hybridization (FISH) and RTqPCR.
  • Biochemical assays to assess enzyme activity, lysosomal pH, and cellular localization.
  • Treatment with specific inhibitors and exogenous supplementation.

Main Results:

  • AKS466 down-regulates SARS-CoV-2 gene expression.
  • SARS-CoV-2 infection deacidifies lysosomal pH via ORF3 protein; AKS466 and fluoxetine reverse this.
  • AKS466 and fluoxetine inhibit acid ceramidase, elevate endo-lysosomal ceramide, and impede viral replication.
  • Specific acid ceramidase inhibitor Ceranib-2 and C6-ceramide supplementation reduce viral replication.

Conclusions:

  • Acid ceramidase is a SARS-CoV-2 host factor essential for viral replication.
  • Fluoxetine and AKS466 exert antiviral effects by inhibiting acid ceramidase and modulating lysosomal function.
  • Targeting acid ceramidase presents a promising therapeutic avenue against SARS-CoV-2.