Topological
Effects and Binding Modes Operating with
Multivalent Iminosugar-Based Glycoclusters and Mannosidases
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Abstract
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 <i>Drosophila melanogaster</i> 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