Identification of novel CERT ligands as potential ceramide trafficking inhibitors
Cécile Santos1, Frédéric Rogriguez, Virginie Garcia
1SPCMIB, UMR-CNRS 5068-Université Paul Sabatier-Toulouse III, 118, route de Narbonne, F-31062 Toulouse Cedex 9 (France).
Abstract:
A highly compartmentalized enzymatic network regulates the pro-apoptotic and proliferative effects of sphingolipids. Over-conversion of ceramide (Cer) correlates with insensitivity to apoptosis signaling (in response to chemotherapy) and to drug resistance of cancer cells. De novo sphingomyelin biosynthesis relies on non-vesicular ceramide trafficking by the CERT (CERamide Transfer) protein. Therefore, blocking CERT transfer, thus leading to increased intracellular ceramide availability, represents a potential anticancer strategy. Our study is based on the implementation of an in vitro binding assay, supported by in silico molecular docking. It constitutes the first attempt to explore at the molecular level for the identification of novel CERT ligands. This approach is the first step toward in silico design and optimization of CERT inhibitor candidates, potentially relevant as innovative ceramide-transfer-targeting therapeutic agents.
Insights
Blocking ceramide transfer protein (CERT) function increases cancer cell ceramide levels, enhancing apoptosis sensitivity. This study identifies novel CERT ligands, paving the way for new anticancer drug development targeting ceramide metabolism.
Area of Science:
- Biochemistry and Molecular Biology
- Cancer Biology
- Drug Discovery
Background:
- Sphingolipids, particularly ceramide (Cer), play a critical role in regulating apoptosis and proliferation.
- Over-conversion of ceramide is linked to chemotherapy resistance and reduced apoptosis signaling in cancer cells.
- The CERamide Transfer (CERT) protein mediates non-vesicular ceramide trafficking, essential for de novo sphingomyelin biosynthesis.
Purpose of the Study:
- To identify novel ligands that inhibit the ceramide transfer activity of the CERT protein.
- To explore potential anticancer strategies by targeting CERT-mediated ceramide transport.
- To lay the groundwork for the in silico design of novel CERT inhibitor candidates.
Main Methods:
- Implementation of an in vitro binding assay to identify CERT ligands.
- Utilizing in silico molecular docking to analyze potential ligand interactions at the molecular level.
- First molecular-level exploration for novel CERT ligand identification.
Main Results:
- The study successfully identified potential novel CERT ligands through integrated in vitro and in silico approaches.
- This research represents the initial molecular-level investigation into CERT ligand discovery.
- The findings provide a foundation for understanding molecular interactions with CERT.
Conclusions:
- Inhibiting CERT-mediated ceramide transfer is a promising anticancer strategy due to increased intracellular ceramide availability.
- The identified ligands are potential starting points for developing innovative therapeutic agents targeting ceramide transfer.
- This work advances the understanding of ceramide biology in cancer and opens avenues for drug design.
