title: Iminosugar-based ceramide mimicry for the design of new CERT START domain ligands.
abstract: 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 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.
authors.affiliation: SPCMIB, UMR5068 CNRS-Université Paul Sabatier-Toulouse III, 118 route de Narbonne, Toulouse F-31062, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Santos
authors.affiliation: Laboratoire de Synthèse Organique et Molécules Bioactives (SYBIO), Université de Strasbourg, CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux (ECPM), 25 rue Becquerel, F-67087 Strasbourg, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Stauffert
authors.affiliation: SPCMIB, UMR5068 CNRS-Université Paul Sabatier-Toulouse III, 118 route de Narbonne, Toulouse F-31062, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Ballereau
authors.affiliation: SPCMIB, UMR5068 CNRS-Université Paul Sabatier-Toulouse III, 118 route de Narbonne, Toulouse F-31062, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Dehoux
authors.affiliation: SPCMIB, UMR5068 CNRS-Université Paul Sabatier-Toulouse III, 118 route de Narbonne, Toulouse F-31062, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rodriguez
authors.affiliation: Laboratoire de Synthèse Organique et Molécules Bioactives (SYBIO), Université de Strasbourg, CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux (ECPM), 25 rue Becquerel, F-67087 Strasbourg, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Bodlenner
authors.affiliation: Laboratoire de Synthèse Organique et Molécules Bioactives (SYBIO), Université de Strasbourg, CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux (ECPM), 25 rue Becquerel, F-67087 Strasbourg, France. Electronic address: philippe.compain@unistra.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Compain
authors.affiliation: SPCMIB, UMR5068 CNRS-Université Paul Sabatier-Toulouse III, 118 route de Narbonne, Toulouse F-31062, France. Electronic address: genisson@chimie.ups-tlse.fr.
authors.forename: Yves
authors.initials: Y
authors.lastname: Génisson
mesh_terms: D066241:Carbon-13 Magnetic Resonance Spectroscopy; D015195:Drug Design; D050111:Imino Sugars / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D062105:Molecular Docking Simulation; D018716:Molecular Mimicry; D020033:Protein Isoforms / Q000378:metabolism*; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D050111:Imino Sugars; D008024:Ligands; D020033:Protein Isoforms
keywords: Ceramide; Ceramide transfer protein CERT; Goodpasture antigen-binding protein GPBP; Iminosugar; Sphingolipid