Facile synthesis of a high-affinity ligand for mammalian hepatic lectin containing three terminal N-acetylgalactosamine residues

A simple cluster glycoside containing three residues of N-acetylgalactosamine with proper inter-residual distances can be a high-affinity ligand for asialoglycoprotein receptor of mammalian liver. YEE(ah-GalNAc)(3) [Lee, R. T., and Lee, Y. C. (1987) Glycoconjugate J. 4, 317-328] is such a ligand having a K-d in the subnanomolar range, and this high-affinity ligand has been successfully utilized in the delivery of gene to the parenchymal cells of the liver [Merwin, J. R., Noell, G. S., Thomas, W. L., Chiou, H. C., DeRome, M. E., McKee, T. D., Spitalny, G. L., and Findeis, M. A. (1994) Bioconjugate Chem. 5, 612-620; Hangeland, J. J., Levis, J. T., Lee, Y. C., and Ts'o, P. O. P. (1995) Bioconjugate Chem. 6, 695-701]. Reported here is a synthetic procedure for an equally effective, homologous trivalent ligand, YDD(G-ah-GalNAc)(3). The advantage offered by this new cluster glycoside is that the synthetic scheme accomplishes purification of reaction intermediates and the product without chromatographic separations. This greatly simplifies the procedure and allows scale-up of the operation at reduced cost of production.