Trivalent, Gal/GalNAc-containing ligands designed for the asialoglycoprotein receptor

A series of novel, fluorescent ligands designed to bind with high affinity and specificity to the asialoglycoprotein receptor (ASGP-R) has been synthesized and tested on human liver cells. The compounds bear three non-reducing, beta-linked Gal or GalNAc moieties linked to flexible spacers for an opt...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2008-05, Vol.16 (9), p.5216-5231
Main Authors: Khorev, Oleg, Stokmaier, Daniela, Schwardt, Oliver, Cutting, Brian, Ernst, Beat
Format: Article
Language:English
Subjects:
Antigens, Tumor-Associated, Carbohydrate - chemistry
Asialoglycoprotein Receptor - chemistry
Asialoglycoprotein Receptor - drug effects
Binding Sites
Cell Line, Tumor
Drug Design
Flow Cytometry - methods
Fluorescence
Humans
Ligands
Liver - drug effects
Liver - pathology
Microscopy, Fluorescence - methods
Molecular Structure
Propylene Glycols - chemical synthesis
Propylene Glycols - chemistry
Propylene Glycols - pharmacology
Stereoisomerism
Structure-Activity Relationship
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Summary:A series of novel, fluorescent ligands designed to bind with high affinity and specificity to the asialoglycoprotein receptor (ASGP-R) has been synthesized and tested on human liver cells. The compounds bear three non-reducing, beta-linked Gal or GalNAc moieties linked to flexible spacers for an optimal spatial interaction with the binding site of the ASGP-R. The final constructs were selectively endocytosed by HepG2 cells derived from parenchymal liver cells-the major human liver cell type-in a process that was visualized with the aid of fluorescence microscopy. Furthermore, the internalization was analyzed with flow cytometry, which showed the process to be receptor-mediated and selective. The compounds described in this work could serve as valuable tools for studying hepatic endocytosis, and are suited as carriers for site-specific drug delivery to the liver.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2008.03.017