title: Design and synthesis of hydrolytically stable multivalent ligands bearing thiodigalactoside analogues for peanut lectin and human galectin-3 binding.
abstract: Herein, we describe the design and synthesis of a novel family of hydrolytically stable glycoclusters bearing thiodigalactoside (TDG) analogues as recognition elements of β-galactoside binding lectins. The TDG analogue was synthesized by thioglycosylation of a 6-S-acetyl-α-D-glucosyl bromide with the isothiouronium salt of 2,3,4,6-tetra-O-acetyl-β-D-galactose. Further propargylation of the TDG analogue allowed the coupling to azido-functionalized oligosaccharide scaffolds through copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) under microwave activation. The final mono-, di-, and tetravalent ligands were resistant to enzymatic hydrolisis by Escherichia coli β-galactosidase. Binding affinities to peanut agglutinin and human galectin-3 were measured by isothermal titration calorimetry which showed K(a) constants in the micromolar range as well as a multivalent effect. Monovalent ligand exhibited a binding affinity higher than that of thiodigalactoside. Docking studies performed with a model ligand on both β-galactoside binding lectins showed additional interactions between the triazole ring and lectin amino acid residues, suggesting a positive effect of this aromatic residue on the biological activity.
authors.affiliation: CIHIDECAR-CONICET, Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires , Pabellón 2, Ciudad Universitaria 1428 Buenos Aires, Argentina.
authors.forename: Alejandro J
authors.initials: AJ
authors.lastname: Cagnoni
authors.forename: José
authors.initials: J
authors.lastname: Kovensky
authors.forename: María Laura
authors.initials: ML
authors.lastname: Uhrig
mesh_terms: D010367:Arachis / Q000737:chemistry*; D001798:Blood Proteins; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D037502:Galectin 3 / Q000737:chemistry*; D037161:Galectins; D006001:Glycoconjugates / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D037102:Lectins / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D013862:Thiogalactosides / Q000737:chemistry*
chemical_list: D001798:Blood Proteins; D037502:Galectin 3; D037161:Galectins; D006001:Glycoconjugates; C428445:LGALS3 protein, human; D037102:Lectins; D008024:Ligands; D013862:Thiogalactosides; C031803:thiodigalactoside