title: 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.
authors.affiliation: Departamento de Química, Facultad de Farmacia, Universidad San Pablo CEU, Boadilla del Monte, 28668, Madrid, Spain.
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Martín-Santamaría
authors.forename: Sabine
authors.initials: S
authors.lastname: André
authors.forename: Eliza
authors.initials: E
authors.lastname: Buzamet
authors.forename: Rémi
authors.initials: R
authors.lastname: Caraballo
authors.forename: Gloria
authors.initials: G
authors.lastname: Fernández-Cureses
authors.forename: Maria
authors.initials: M
authors.lastname: Morando
authors.forename: João P
authors.initials: JP
authors.lastname: Ribeiro
authors.forename: Karla
authors.initials: K
authors.lastname: Ramírez-Gualito
authors.forename: Beatriz
authors.initials: B
authors.lastname: de Pascual-Teresa
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Cañada
authors.forename: Margarita
authors.initials: M
authors.lastname: Menéndez
authors.forename: Olof
authors.initials: O
authors.lastname: Ramström
authors.forename: Jesús
authors.initials: J
authors.lastname: Jiménez-Barbero
authors.forename: Dolores
authors.initials: D
authors.lastname: Solís
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Gabius
mesh_terms: D000818:Animals; D001665:Binding Sites; D002417:Cattle; D045744:Cell Line, Tumor; D006801:Humans; D037102:Lectins / Q000737:chemistry* / Q000378:metabolism; D008954:Models, Biological; D056004:Molecular Dynamics Simulation; D010944:Plants / Q000737:chemistry / Q000378:metabolism; D013862:Thiogalactosides / Q000737:chemistry*; D014118:Toxins, Biological / Q000737:chemistry* / Q000378:metabolism; D028182:Viscum album / Q000378:metabolism
chemical_list: D037102:Lectins; D013862:Thiogalactosides; D014118:Toxins, Biological; C031803:thiodigalactoside