Topological effects and binding modes operating with multivalent iminosugar-based glycoclusters and mannosidases.
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 α-mannosidase (JBαMan) and the biologically relevant class II α-mannosidases from Drosophila melanogaster belonging to glycohydrolase family 38, namely Golgi α-mannosidase ManIIb (GM) and lysosomal α-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 JBαMan, 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 JBαMan shed light on the multivalent binding mode. The multivalent compounds were shown to promote the formation of JBαMan aggregates with different sizes and shapes. The dimeric nature of the JBαMan allows such intermolecular cross-linking mechanisms to occur.
LUNAM Université , CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, UFR des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France.
Yoan
Y
Brissonnet
Carmen
C
Ortiz Mellet
Sandrine
S
Morandat
M Isabel
MI
Garcia Moreno
David
D
Deniaud
Susan E
SE
Matthews
Sébastien
S
Vidal
Sergej
S
Šesták
Karim
K
El Kirat
Sébastien G
SG
Gouin
D000818:Animals; D001665:Binding Sites; D004331:Drosophila melanogaster; D050111:Imino Sugars / Q000737:chemistry*; D008361:Mannosidases / Q000737:chemistry*; D018625:Microscopy, Atomic Force
D050111:Imino Sugars; D008361:Mannosidases