title: A new N-acetylgalactosamine containing peptide as a targeting vehicle for mammalian hepatocytes via asialoglycoprotein receptor endocytosis.
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-alpha-(ah-Ac3GalNAc)-L-glutamate allowed access to the target compound YEEE(alpha-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(alpha-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.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Ying-Ta
authors.initials: YT
authors.lastname: Wu
authors.forename: Weir-Torn
authors.initials: WT
authors.lastname: Jiaang
authors.forename: Kuo-Ging
authors.initials: KG
authors.lastname: Lin
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Huang
authors.forename: Chin-Hsien
authors.initials: CH
authors.lastname: Chang
authors.forename: Ying-Ling
authors.initials: YL
authors.lastname: Sun
authors.forename: Kuo-Hsien
authors.initials: KH
authors.lastname: Fan
authors.forename: Wei-Chuan
authors.initials: WC
authors.lastname: Hsu
authors.forename: Hsin-Ell
authors.initials: HE
authors.lastname: Wang
authors.forename: Shwu-Bin
authors.initials: SB
authors.lastname: Lin
authors.forename: Shui-Tein
authors.initials: ST
authors.lastname: Chen
mesh_terms: D000116:Acetylgalactosamine / Q000737:chemistry; D000818:Animals; D037263:Asialoglycoprotein Receptor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D004705:Endocytosis; D006020:Glycopeptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
chemical_list: D037263:Asialoglycoprotein Receptor; D004337:Drug Carriers; D006020:Glycopeptides; D008024:Ligands; C092360:tyrosyl(glutamyl)glutamate tris(N-acetylgalactosamineaminohexylglycoside)amide; C507314:tyrosyl-(alpha-(N-acetylaminogalactopyranosyloxyhexylamino),gamma-(alpha-(N-acetylaminogalactopyranosyloxyhexylamino),gamma-(alpha-(N-acetylaminogalactopyranosyloxyhexylamino)glutamyl))glutamyl)glutamate; D000116:Acetylgalactosamine