Topological effects and binding modes operating with multivalent iminosugar-based glycoclusters and mannosidases

Area of Science:

• Carbohydrate chemistry
• Enzymology
• Glycobiology

Background:

• Multivalent iminosugars are explored for glycosidase inhibition, offering potential affinity enhancements.
• Achieving enzyme selectivity with multivalency is appealing but requires understanding binding modes.

Purpose of the Study:

• Develop tetra- and octavalent iminosugar probes with defined topologies.
• Assess binding affinities toward specific glycosidases, including Jack Bean α-mannosidase (JBαMan) and Drosophila melanogaster class II α-mannosidases (GM and LM).
• Investigate the impact of spatial distribution on inhibitory activity and selectivity.

Main Methods:

• Synthesis of multivalent iminosugar probes (tetra- and octavalent).
• Enzyme inhibition assays against JBαMan, Golgi α-mannosidase (GM), and lysosomal α-mannosidase (LM).
• Dynamic light scattering (DLS) and atomic force microscopy (AFM) to study binding modes.

Main Results:

• Inhibitory profiles varied significantly based on the spatial distribution of iminosugars, even with identical valencies.
• The best tetravalent compound demonstrated an 800-fold increase in inhibitory potency against JBαMan compared to the monovalent reference.
• This compound also enhanced inhibitory activity and selectivity for GM over LM.
• DLS and AFM revealed that multivalent compounds induced JBαMan aggregation through intermolecular cross-linking.

Conclusions:

• Spatial arrangement of multivalent iminosugars is critical for fine-tuning enzymatic inhibitory activity and selectivity.
• Multivalency presents a viable strategy for developing therapeutic Golgi α-mannosidase (GM) inhibitors without affecting lysosomal α-mannosidases (LM).
• The observed aggregation of JBαMan suggests a mechanism involving intermolecular cross-linking facilitated by the enzyme's dimeric nature.