A New N-Acetylgalactosamine Containing Peptide as a Targeting Vehicle for Mammalian Hepatocytes Via Asialoglycoprotein Receptor Endocytosis

Ying-Ta      Wu; Weir-Torn      Jiaang; Kuo-Ging      Lin; Chun-Ming      Huang; Chin-Hsien      Chang; Ying-Ling      Sun; Kuo-Hsien      Fan; Wei-Chuan      Hsu; Hsin-Ell      Wang; Shwu-Bin      Lin

doi:10.2174/1567201043479939

Abstract

Galactoside-containing cluster ligands have high affinity for asialoglycoprotein receptors (ASGP-r), which are found in abundance in mammalian parenchymal liver cells. These ligands may be conjugated with a therapeutic drug to improve the efficiency of delivery to diseased liver cells. This report describes a new synthetic route towards clustering glycopeptides containing N-acetyl-D-galactosamine (GalNAc). The building block Fmoc-α-(ah-Ac3GalNAc)-Lglutamate allowed access to the target compound YEEE(α-ah-GalNAc)3, a structural mimic of YEE(ah-GalNAc)3, via solid phase peptide synthesis (SPPS). Fatty acid, poly-lysine, fluorescein and biotin conjugates further demonstrate the facility of the described method. Using fluorescein labeling and 131I labeling, in vitro and in vivo assays confirmed that YEEE(a-ah-GalNAc)3 possesses both specificity and affinity to the liver, similar to the agent YEE(ah-GalNAc)3, which targets liver lesions. The synthesis described in this report represents a considerable improvement in synthesizing a ligand for ASGP-r by simplifying both the preparation of the starting material and the procedure for conjugating the galactosidase cluster to drugs.

Keywords: asialoglycoprotein, endocytosis, glycopeptide, hepatocyte

« Previous Next »