Iminosugar-based ceramide mimicry for the design of new CERT START domain ligands

Publication date: Available online 14 February 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Cécile Santos, Fabien Stauffert, Stéphanie Ballereau, Cécile Dehoux, Frédéric Rodriguez, Anne Bodlenner, Philippe Compain, Yves Génisson
The enigmatical dichotomy between the two CERT/GPBP protein isoforms, their vast panel of biological implications and the scarcity of known antagonist series call for new ligand chemotypes identification. We report the design of iminosugar-based ceramide mimics for the development of new START domain ligands potentially targeting either protein isoforms. Strategic choice of i) an iminoxylitol core structure and ii) the positioning of two dodecyl residues led to an extent of protein binding comparable to that of the natural cargo lipid ceramide or the archetypical inhibitor HPA-12. Molecular docking study evidenced a possible mode of protein binding fully coherent with the one observed in crystalline co-structures of known ligands. The present study thus paves the way for cellular CERT inhibition activity studies en route to the development of pharmacological tools aiming at deciphering the respective function and therapeutic potential of the two CERT/GPBP protein isoforms.

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