Inhibiteurs neutres de glycosyltransférases et inhibition de l’O-‐GlcNAc-‐Transferase (OGT) Shuai Wang,1 Dominique Lafont,1 Ofelia Maniti,1 David L. Shen,2 Yun Shi,2 Anne-‐Sophie Vercoutter-‐ Edouart,3 Marlène Mortuaire,3 David Vocadlo,2 B. Mario Pinto,2 Agnès Girard-‐Egrot,1 Tony Lefebvre,3 Sébastien Vidal*1 1 Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR 5246, CNRS, Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne, France 2 Departments of Chemistry and Molecular Biology & Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6 3 Unité de Glycobiologie Structurale et Fonctionnelle, UMR CNRS/USTL 8576, IFR 147, Avenue Mendeleïev, Université des Sciences et Technologies de Lille, 59655 Villeneuve d'Ascq, France Glycosyltransferase is an important class of enzyme in living organisms responsible for the biosynthesis of oligosaccharides, polysaccharides and glycoconjugates. As more and more carbohydrate related biological processes are elucidated, there is great interest to define the biological roles of a given carbohydrate and examine its potential therapeutic applications. The present study reports the design of two novel types of glycosyltransferase sugar nucleotide diphosphate substrates incorporating a ‘neutral’ pyridine or amino-‐acid moiety as the pyrophosphate surrogate in order to provide cell permeable substrates for potential in cellulo or in vivo applications.1 The syntheses of “neutral” GTs inhibitors were performed using a combination of conjugations through O-‐glycoside bond,2 amide bond or triazole functionalities. A total number of 26 “neutral” GT inhibitors were prepared.3,4 The evaluation of inhibition towards five galactosyltransferases3 and human O-‐GlcNAc-‐transferase4 (OGT) revealed moderate inhibitions in the micromolar range. More interestingly, co-‐crystallyzation could be achieved for the most potent compounds in complex with a glycosyltransferase.3 The designed ‘neutral’ pyridine linker could chelate the manganese cation involved in the enzyme catalytic site. Whereas the sugar head-‐group was oriented away from the position found in the related complex with natural substrate (UDP-‐Gal) indicating a new binding mode. The concept of ‘neutral’ inhibitor was examined by an artificial cell membrane penetration test.4 [1] Wang, S.; Vidal S. “Recent design of glycosyltransferase inhibitors” in “Carbohydrate Chemistry: Specialist Periodical Reports” Rauter A. P., Lindhorst T. Eds.; RSC Publishing : Cambridge, 2013, 39, 78-‐101. [2] Wang, S.; Lafont, D.; Rahkila, J.; Picod, B.; Leino, R. and Vidal, S. Carbohydr. Res., 2013, 372, 35-‐46. [3] Wang, S.; Cuesta-‐Seijo, J. A.; Lafont, D.; Palcic, M. M. and Vidal S. Chem. Eur. J. 2013, 19, 15346-‐15357. [4] Wang, S.; Shen, D. L.; Lafont, D.; Vercoutter-‐Edouart, A-‐S.; Mortuaire, M.; Shi, Y.; Maniti, O.; Girard-‐Egrot, A.; Lefebvre, T.; Pinto, B. M.; Vocadlo, D. and Vidal, S. MedChemComm, 2014, DOI: 10.1039/C4MD00063C.
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