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Article Dans Une Revue Angewandte Chemie International Edition Année : 2022

Discovery and mechanism of action of small molecule inhibitors of ceramidases

Robert Healey
Xiaojing Cong
Shibom Basu
Cedric Leyrat
  • Fonction : Auteur
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Jérôme Golebiowski
Cherine Bechara

Résumé

Sphingolipid metabolism is tightly controlled by enzymes to regulate essential processes in human physiology. The central metabolite is ceramide, a pro-apoptotic lipid catabolized by ceramidase enzymes to produce pro-proliferative sphingosine-1phosphate. Alkaline ceramidases are transmembrane enzymes that recently attracted attention for drug development in fatty liver diseases. However, due to their hydrophobic nature, no specific small molecule inhibitors have been reported. Here, we present the discovery and mechanism of action of the first drug-like inhibitors of alkaline ceramidase 3 (ACER3). In particular, we chemically engineered novel fluorescent ceramide substrates enabling screening of large compound libraries and characterized enzyme:inhibitor interactions using mass spectrometry and MD simulations. In addition to reveal a new paradigm for inhibition of lipid metabolising enzymes with nonlipidic small molecules, our data lay the ground for targeting ACER3 in drug discovery efforts.

Dates et versions

hal-03406152 , version 1 (27-10-2021)

Identifiants

Citer

Robert Healey, Essa Saied, Xiaojing Cong, Gergely Karsai, Ludovic Gabellier, et al.. Discovery and mechanism of action of small molecule inhibitors of ceramidases. Angewandte Chemie International Edition, 2022, 61 (2), pp.e202109967. ⟨10.1002/anie.202109967⟩. ⟨hal-03406152⟩
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