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

Sonsoles Martín-Santamaría; Sabine André; Eliza Buzamet; Rémi Caraballo; Gloria Fernández-Cureses; Maria Morando; João P. Ribeiro; Karla Ramírez-Gualito; Beatriz de Pascual-Teresa; F. Javier Cañada; Margarita Menéndez; Olof Ramström; Jesús Jiménez-Barbero; Dolores Solís; Hans-Joachim Gabius

doi:10.1039/C0OB01235A

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

Sonsoles Martín-Santamaría,^a Sabine André,^b Eliza Buzamet,^cd Rémi Caraballo,^e Gloria Fernández-Cureses,^c Maria Morando,^f João P. Ribeiro,^f Karla Ramírez-Gualito,^f Beatriz de Pascual-Teresa,^a F. Javier Cañada,^f Margarita Menéndez,^cd Olof Ramström,^e Jesús Jiménez-Barbero,*^f Dolores Solís^cd and Hans-Joachim Gabius^b

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* Corresponding authors

^a Departamento de Química, Facultad de Farmacia, Universidad San Pablo CEU, Boadilla del Monte, Madrid, Spain

^b Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig-Maximilians-University Munich, Veterinärstr. 13, Munich, Germany

^c Instituto de Química Física Rocasolano, Consejo Superior de Investigaciones Científicas, Serrano 119, Madrid, Spain

^d Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Bunyola, Mallorca, Illes Balears, Spain

^e Department of Chemistry, KTH-Royal Institute of Technology, Teknikringen 30, Stockholm, Sweden

^f Chemical and Physical Biology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, Madrid, Spain

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.

Organic & Biomolecular Chemistry

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

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

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