期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 25, 期 6, 页码 1984-1989出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2017.02.026
关键词
Sphingolipid; Ceramide; Ceramide transfer protein CERT; Goodpasture antigen-binding protein GPBP; Iminosugar
资金
- CNRS
- University Paul Sabatier-Toulouse III
- University of Strasbourg
- French Department of Research
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. (C) 2017 Elsevier Ltd. All rights reserved.
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