Topological Effects and Binding Modes Operating with Multivalent Iminosugar-Based Glycoclusters and Mannosidases

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• 作者：Yoan Brissonnet ; Carmen Ortiz Mellet ; Sandrine Morandat ; M. Isabel Garcia Moreno ; David Deniaud ; Susan E. Matthews ; S茅bastien Vidal ; Sergej 艩est谩k ; Karim El Kirat ; S茅bastien G. Gouin
• 刊名：Journal of the American Chemical Society
• 出版年：2013
• 出版时间：December 11, 2013
• 年：2013
• 卷：135
• 期：49
• 页码：18427-18435
• 全文大小：570K
• 年卷期：v.135,no.49(December 11, 2013)
• ISSN：1520-5126

文摘

Multivalent iminosugars have been recently explored for glycosidase inhibition. Affinity enhancements due to multivalency have been reported for specific targets, which are particularly appealing when a gain in enzyme selectivity is achieved but raise the question of the binding mode operating with this new class of inhibitors. Here we describe the development of a set of tetra- and octavalent iminosugar probes with specific topologies and an assessment of their binding affinities toward a panel of glycosidases including the Jack Bean 伪-mannosidase (JB伪Man) and the biologically relevant class II 伪-mannosidases from Drosophila melanogaster belonging to glycohydrolase family 38, namely Golgi 伪-mannosidase ManIIb (GM) and lysosomal 伪-mannosidase LManII (LM). Very different inhibitory profiles were observed for compounds with identical valencies, indicating that the spatial distribution of the iminosugars is critical to fine-tune the enzymatic inhibitory activity. Compared to the monovalent reference, the best multivalent compound showed a dramatic 800-fold improvement in the inhibitory potency for JB伪Man, which is outstanding for just a tetravalent ligand. The compound was also shown to increase both the inhibitory activity and the selectivity for GM over LM. This suggests that multivalency could be an alternative strategy in developing therapeutic GM inhibitors not affecting the lysosomal mannosidases. Dynamic light scattering experiments and atomic force microscopy performed with coincubated solutions of the compounds with JB伪Man shed light on the multivalent binding mode. The multivalent compounds were shown to promote the formation of JB伪Man aggregates with different sizes and shapes. The dimeric nature of the JB伪Man allows such intermolecular cross-linking mechanisms to occur.