Investigation of original multivalent iminosugars as pharmacological chaperones for the treatment of Gaucher disease

Multivalent iminosugars conjugated with a morpholine moiety and/or designed as prodrugs have been prepared and evaluated as new classes of pharmacological chaperones for the treatment of Gaucher disease. This study further confirms the interest of the prodrug concept and shows that the addition of a lysosome-targeting morpholine unit into iminosugar cluster structures has no significant impact on the chaperone activity on Gaucher cell

High‐Mannose Oligosaccharide Hemimimetics that Recapitulate the Conformation and Binding Mode to Concanavalin A, DC‐SIGN and Langerin

Abstract The “carbohydrate chemical mimicry” exhibited by sp 2 ‐iminosugars has been utilized to develop practical syntheses for analogs of the branched high‐mannose‐type oligosaccharides (HMOs) Man 3 and Man 5 . In these compounds, the terminal nonreducing Man residues have been substituted with 5,6‐oxomethylidenemannonojirimycin (OMJ) motifs. The resulting oligomannoside hemimimetic accurately reproduce the structure, configuration, and conformational behavior of the original mannooligosaccharides, as confirmed by NMR and computational techniques. Binding studies with mannose binding lectins, including concanavalin A, DC‐SIGN, and langerin, by enzyme‐linked lectin assay and surface plasmon resonance revealed significant variations in their ability to accommodate the OMJ unit in the mannose binding site. Intriguingly, OMJMan segments demonstrated “in line” heteromultivalent effects during binding to the three lectins. Similar to the mannobiose (Man 2 ) branches in HMOs, the binding modes involving the external or internal monosaccharide unit at the carbohydrate binding‐domain exist in equilibrium, facilitating sliding and recapture processes. This equilibrium, which influences the multivalent binding of HMOs, can be finely modulated upon incorporation of the OMJ sp 2 ‐iminosugar caps. As a proof of concept, the affinity and selectivity towards DC‐SIGN and langerin were adjustable by presenting the OMJMan epitope in platforms with diverse architectures and valencies