Symmetric dithiodigalactoside: strategic combination of binding studies and detection of selectivity between a plant toxin and human lectins

Abstract

Thioglycosides offer the advantage over O-glycosides to be resistant to hydrolysis. Based on initial evidence of this recognition ability for glycosyldisulfides by screening dynamic combinatorial libraries, we have now systematically studied dithiodigalactoside on a plant toxin (Viscum album agglutinin) and five human lectins (adhesion/growth-regulatory galectins with medical relevance e.g. in tumor progression and spread). Inhibition assays with surface-presented neoglycoprotein and in solution monitored by saturation transfer difference NMR spectroscopy, flanked by epitope mapping, as well as isothermal titration calorimetry revealed binding properties to VAA (K a : 1560 ± 20 M -1 ). They were reflected by the structural model and the affinity on the level of toxin-exposed cells. In comparison, galectins were considerably less reactive, with intrafamily grading down to very minor reactivity for tandem-repeat-type galectins, as quantitated by radioassays for both domains of galectin-4. Model building indicated contact formation to be restricted to only one galactose moiety, in contrast to thiodigalactoside. The tested glycosyldisulfide exhibits selectivity between the plant toxin and the tested human lectins, and also between these proteins. Therefore, glycosyldisulfides have potential as chemical platform for inhibitor design.

Bi- to tetravalent glycoclusters: synthesis, structure–activity profiles as lectin inhibitors and impact of combining both valency and headgroup tailoring on selectivity

“…Of note, set in relation to the plant toxin, the case of dithiodigalactoside, which shows low-affinity binding, if at all, to human galectins, exemplifies the possibility for markedly different headgroup affinities despite presence of galactose and thus enabling the targeting of the toxin with a galactose-based compound while avoiding side effects that would result from binding to galectins. 30 …”

Conformational Selection in Glycomimetics: Human Galectin‐1 Only Recognizes syn‐Ψ‐Type Conformations of β‐1,3‐Linked Lactose and Its C‐Glycosyl Derivative

“…Therefore, it is very likely that these hydrogen bonds could be the key driving force for the conformational selection process that permits the recognition of the minor conformer of the C ‐glycosyl molecule in free solution. In fact, the efficient recognition of other disaccharides, such as galactosyl xylopyranosides20 or thio‐/dithio‐based glycomimetics21 by hGal‐1 also requires the presence of a properly oriented hydroxyl group to establish the intermolecular contacts. Otherwise, no interaction of hGal‐1, even with non‐reducing Gal‐containing molecules, can take place, as observed for Gal‐S‐S‐Gal 21.…”

“…In fact, the efficient recognition of other disaccharides, such as galactosyl xylopyranosides20 or thio‐/dithio‐based glycomimetics21 by hGal‐1 also requires the presence of a properly oriented hydroxyl group to establish the intermolecular contacts. Otherwise, no interaction of hGal‐1, even with non‐reducing Gal‐containing molecules, can take place, as observed for Gal‐S‐S‐Gal 21. In this case, an interaction of the second Gal unit with Arg48 and Glu71 was judged to be impossible.…”

Advanced NMR Techniques: Defining Carbohydrate Structures and Ligand–Receptor Interactions

“…In the best situation, experimental information from ligand-based and receptor-based experiments should be available, thus providing the full experimental information required to derive a precise 3D structure [91,92]. In other cases, only experimental information on the bound ligand conformation is accessible and the structure of the receptor has to be deduced from alternative methods [93]. In these cases, the combination of docking protocols and MD simulations is of paramount importance [94].…”