title: 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.
authors.affiliation: LG-2A FRE-CNRS 3517, Institut de Chimie de Picardie, Université de Picardie Jules Verne, 33 Rue Saint-Leu, 80039 Amiens Cedex 1 (France).
authors.forename: Marc
authors.initials: M
authors.lastname: François-Heude
authors.forename: Alejandro
authors.initials: A
authors.lastname: Méndez-Ardoy
authors.forename: Virginie
authors.initials: V
authors.lastname: Cendret
authors.forename: Pierre
authors.initials: P
authors.lastname: Lafite
authors.forename: Richard
authors.initials: R
authors.lastname: Daniellou
authors.forename: Carmen
authors.initials: C
authors.lastname: Ortiz Mellet
authors.forename: José M
authors.initials: JM
authors.lastname: García Fernández
authors.forename: Vincent
authors.initials: V
authors.lastname: Moreau
authors.forename: Florence
authors.initials: F
authors.lastname: Djedaïni-Pilard
mesh_terms: D057930:Click Chemistry; D006801:Humans; D037102:Lectins / Q000737:chemistry*; D008358:Mannose / Q000138:chemical synthesis* / Q000737:chemistry*; D009844:Oligosaccharides / Q000737:chemistry*
chemical_list: D037102:Lectins; D009844:Oligosaccharides; D008358:Mannose
keywords: carbohydrates; click chemistry; glycoconjugates; oligosaccharides; structure-activity relationships