A new N-acetylgalactosamine containing peptide as a targeting vehicle for mammalian hepatocytes via asialoglycoprotein receptor endocytosis.
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.
Wu
Ying-Ta
YT
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
Jiaang
Weir-Torn
WT
Lin
Kuo-Ging
KG
Huang
Chun-Ming
CM
Chang
Chin-Hsien
CH
Sun
Ying-Ling
YL
Fan
Kuo-Hsien
KH
Hsu
Wei-Chuan
WC
Wang
Hsin-Ell
HE
Lin
Shwu-Bin
SB
Chen
Shui-Tein
ST
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
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