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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
KTH, School of Chemical Science and Engineering (CHE), Chemistry.
KTH, School of Chemical Science and Engineering (CHE), Chemistry.
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2006 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, Vol. 14, 6314-6326 p.Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
2006. Vol. 14, 6314-6326 p.
Keyword [en]
agglutinin, combinatorial chemistry, drug design, galectin, glycosyldisulfide, neoglycoprotein, dynamic chemistry
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-6387DOI: 10.1016/j.bmc.2006.05.045ISI: 000240615300018Scopus ID: 2-s2.0-33747134305OAI: oai:DiVA.org:kth-6387DiVA: diva2:11083
Note
QC 20100915Available from: 2006-11-22 Created: 2006-11-22 Last updated: 2010-09-15Bibliographically approved
In thesis
1. Carbohydrate Synthesis and Study of Carbohydrate-Lectin Interactions Using QCM Biosensors and Microarray Technologies
Open this publication in new window or tab >>Carbohydrate Synthesis and Study of Carbohydrate-Lectin Interactions Using QCM Biosensors and Microarray Technologies
2006 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

Interactions between carbohydrates and proteins are increasingly being recognized as crucial in many biological processes, such as cellular adhesion and communication. In order to investigate the interactions of carbohydrates and proteins, the development of efficient analytic technologies, as well as novel strategies for the synthesis of carbohydrates, have to be explored. To date, several methods have been exploited to analyze interactions of carbohydrates and proteins, for example, biosensors, nuclear magnetic resonance (NMR); enzyme-linked immunosorbent assays (ELISA), X-ray crystallography and array technologies. This thesis describes the development of novel strategies for the synthesis of carbohydrates, as well as new efficient strategies to Quartz Crystal Microbalance- (QCM-) biosensors and carbohydrate microarrays technologies. These methodologies have been used to probe carbohydrate-lectin-interactions for a range of plant and animal lectins.

Place, publisher, year, edition, pages
Stockholm: KTH, 2006. 106 p.
Series
Trita-IOK, ISSN 1100-7974 ; 2006:106
Keyword
Lectins; Carbohydrates; Molecular recognition; Biosensors; Quartz crystal microbalance; Carbohydrate microarrays.
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-4177 (URN)91-7178-503-5 (ISBN)
Public defence
2006-12-01, D3, Lindstedtsvägen 5, Stockholm, 10:00
Opponent
Supervisors
Note
QC 20100915Available from: 2006-11-22 Created: 2006-11-22 Last updated: 2011-09-05Bibliographically approved

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