Synthesis of High‐Mannose Oligosaccharide Analogues through Click Chemistry: True Functional Mimics of Their Natural Counterparts Against Lectins?

Abstract

Terminal "high-mannose oligosaccharides" are involved in a broad range of biological and pathological processes, from sperm-egg fusion to influenza and human immunodeficiency virus infections. In spite of many efforts, their synthesis continues to be very challenging and actually represents a major bottleneck in the field. Whereas multivalent presentation of mannopyranosyl motifs onto a variety of scaffolds has proven to be a successful way to interfere in recognition processes involving high-mannose oligosaccharides, such constructs fail at reproducing the subtle differences in affinity towards the variety of protein receptors (lectins) and antibodies susceptible to binding to the natural ligands. Here we report a family of functional high-mannose oligosaccharide mimics that reproduce not only the terminal mannopyranosyl display, but also the core structure and the branching pattern, by replacing some inner mannopyranosyl units with triazole rings. Such molecular design can be implemented by exploiting "click" ligation strategies, resulting in a substantial reduction of synthetic cost. The binding affinities of the new "click" high-mannose oligosaccharide mimics towards two mannose specific lectins, namely the plant lectin concanavalin A (ConA) and the human macrophage mannose receptor (rhMMR), have been studied by enzyme-linked lectin assays and found to follow identical trends to those observed for the natural oligosaccharide counterparts. Calorimetric determinations against ConA, and X-ray structural data support the conclusion that these compounds are not just another family of multivalent mannosides, but real "structural mimics" of the high-mannose oligosaccharides.

Design of Engineered Cyclodextrin Derivatives for Spontaneous Coating of Highly Porous Metal-Organic Framework Nanoparticles in Aqueous Media

“…It is important to highlight that the selected model lectin, ConA, and the actual human macrophage mannose receptor (hMMR) are different, both at structural and binding mechanism levels, and thus, any extrapolation from the former to the latter should be made with care. However, recently it has been reported that affinities of a series of mimics for both lectins in solution are qualitatively similar [56,57], which supports our choice.…”

Pharmacological Chaperones for the Treatment of α-Mannosidosis

“…We keep in mind that triazole rings have been previously found to preserve the recognition abilities of oligosaccharide mimetics towards receptors and enzymes, behaving as monosaccharide surrogates. 53 For the purpose of this study, we have chosen -cyclodextrin (CD) as a platform for multivalency generation because of its biocompatibility and amenability to regioselective chemical functionalization. 54 The 6 Imonosubstituted CD conjugate 6 was designed to duly probe the impact of the CD macroring in the enzyme binding capabilities.…”

Chitooligosaccharide Synthesis Using an Ionic Tag

“…All attempts using hydrogenolysis under H 2 catalyzed by Pd/C or Pd black with various solvents in an acidic medium failed to remove the ionic tag, and complex mixtures were formed in all cases. Only the very recently developed method of transfer hydrogenolysis using resin‐supported ammonium formate and palladium on charcoal under microwave heating27 led to cleavage of the ionic tag, along with the O ‐benzyl and N ‐benzyloxycarbonyl groups, accompanied by partial de‐ O ‐acetylation. Removal of the remaining O ‐acetyl groups by methanolysis produced target chitooligosaccharide 2 in a yield of 13 % over four steps from protected intermediate 19 , after a single chromatographic purification on silica gel from the starting monosaccharide 7 (10 steps) (Table 2, entry 1).…”