Lectin-Mediated Drug Targeting: Selection of Valency, Sugar Type (Gal/Lac), and Spacer Length for Cluster Glycosides as Parameters to Distinguish Ligand Binding to C-Type Asialoglycoprotein Receptors and Galectins |
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Authors: | Sabine André Benoît Frisch Herbert Kaltner Débora Lima Desouza Francis Schuber Hans-J Gabius |
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Institution: | (1) Institut für Physiologische Chemie, Tierärztliche Fakultät, Ludwig-Maximilians-Universität, Veterinärstr. 13, D-80539 München, Germany;(2) Laboratoire de Chimie Bioorganique (UMR 7514 CNRS), Faculté de Pharmacie, 74 route du Rhin, F-67400 Illkirch, France;(3) Institut für Physiologische Chemie, Tierärztliche Fakultät, Ludwig-Maximilians-Universität, Veterinärstr. 13, D-80539 München, Germany |
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Abstract: | Purpose. Common oligosaccharides of cellularglycoconjugates are ligands for more than one type of endogenous lectin.Overlapping specificities to -galactosides of C-type lectins andgalectins can reduce target selectivity of carbohydrate-ligand-dependentdrug targeting. The purpose of this study is to explore distinct features ofligand presentation and structure for design of cluster glycosides todistinguish between asialoglycoprotein-specific (C-type) lectins andgalectins.
Methods. Extent of binding of labeled sugar receptors totwo types of matrix-immobilized (neo)glycoproteins and to cells wasevaluated in the absence and presence of competitive inhibitors. This panelcomprised synthetic mono-, bi-, and trivalent glycosides with two spacerlengths and galactose or lactose as ligand part.
Results. In contrast to C-type lectins of hepatocytes andmacrophages, bi- and trivalent glycosides do not yield a notable glycosidecluster effect for galectins-1 and -3. Also, theseCa2+-independent galactoside-binding proteins prefer to homein on lactose-bearing glycosides relative to galactose as ligand, whilespacer length requirements were rather similar.
Conclusions. Trivalent cluster glycosides with Gal/GalNAcas ligand markedly distinguish between C-type lectins and galectins.Undesired side reactivities to galectins for C-type lectin drug deliverywill thus be minimal. |
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Keywords: | asialoglycoprotein receptor cluster glycoside drug targeting galectin lectin neoglycoprotein |
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