Discovery and Mechanism of Action of Small Molecule Inhibitors of Ceramidases. (25th November 2021)

• Record Type: Journal Article
• Authors: Healey, Robert D.; Saied, Essa M.; Cong, Xiaojing; Karsai, Gergely; Gabellier, Ludovic; Saint‐Paul, Julie; Del Nero, Elise; Jeannot, Sylvain; Drapeau, Marion; Fontanel, Simon; Maurel, Damien; Basu, Shibom; Leyrat, Cedric; Golebiowski, Jérôme; Bossis, Guillaume; Bechara, Cherine; Hornemann, Thorsten; Arenz, Christoph; Granier, Sebastien
• Is Part Of: Angewandte Chemie. Volume 134:Number 2(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-11-25
• Subjects: ceramidase -- FRET screening assay -- intramembrane enzyme inhibition -- lipid metabolism -- structural dynamics; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.202109967
• Languages: English
• ISSNs: 0044-8249

Abstract

Abstract: 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‐1‐phosphate. 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. 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 revealing a new paradigm for inhibition of lipid metabolising enzymes with non‐lipidic small molecules, our data lay the ground for targeting ACER3 in drug discovery efforts. Abstract : Use of synthetic fluorescent ceramide molecules allows the discovery of the first selective drug‐like small molecule inhibitors for alkaline ceramidase 3, an intra‐membrane enzyme involved in sphingolipid metabolism in health and disease. These inhibitors represent a new paradigm for controlling lipid metabolism with drug‐like small molecules targeting conformationally dynamic membrane proteins.