Glycosyldisulfides from dynamic combinatorial libraries as O-glycoside mimetics for plant and endogenous lectins: their reactivities in solid-phase and cell assays and conformational analysis by molecular dynamics simulations.
Dynamic combinatorial library design exploiting the thiol-disulfide exchange readily affords access to glycosyldisulfides. In order to reveal lectin-binding properties of this type of non-hydrolyzable sugar derivative, libraries originating from a mixture of common building blocks of natural glycans and thiocompounds were tested against three plant agglutinins with specificity to galactose, fucose or N-acetylgalactosamine, respectively, in a solid-phase assay. Extent of lectin binding to matrix-immobilized neoglycoprotein presenting the cognate sugar could be reduced, and evidence for dependence on type of carbohydrate was provided by dynamic deconvolution. Glycosyldisulfides also maintained activity in assays of increased physiological relevance, that is, using native tumor cells and also adding to the test panel an endogenous lectin (galectin-3) involved in tumor spread and cardiac dysfunction. N-Acetylgalactosamine was pinpointed as the most important building block of libraries for the human lectin and the digalactoside as most potent compound acting on the toxic mistletoe agglutinin which is closely related to the biohazard ricin. Because this glycosyldisulfide, which even surpasses lactose in inhibitory capacity, rivals thiodigalactoside as inhibitor, their degrees of intramolecular flexibility were comparatively analyzed by computational calculations. Molecular dynamics runs with explicit consideration of water molecules revealed a conspicuously high degree of potential for shape alterations by the disulfide's three-bond system at the interglycosidic linkage. The presented evidence defines glycosyldisulfides as biologically active ligands for lectins.
André
Sabine
S
Institut für Physiologische Chemie, Tierärztliche Fakultät, Ludwig-Maximilians-Universität München, Veterinärstr. 13, D-80539 München, Germany.
Pei
Zhichao
Z
Siebert
Hans-Christian
HC
Ramström
Olof
O
Gabius
Hans-Joachim
HJ
D001665:Binding Sites; D002236:Carbohydrate Conformation; D002460:Cell Line; D002478:Cells, Cultured; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D004220:Disulfides / Q000737:chemistry*; D006001:Glycoconjugates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006027:Glycosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D037102:Lectins / Q000737:chemistry*; D018716:Molecular Mimicry; D013329:Structure-Activity Relationship; D013499:Surface Properties
D004220:Disulfides; D006001:Glycoconjugates; D006027:Glycosides; D037102:Lectins