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

Bioorg Med Chem. 2008 May 1;16(9):5216-31. doi: 10.1016/j.bmc.2008.03.017. Epub 2008 Mar 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Antigens, Tumor-Associated, Carbohydrate
  • Asialoglycoprotein Receptor
  • Ligands
  • Propylene Glycols
  • Thomsen-Friedenreich antigen