Synthesis of Antisense Oligonucleotides Conjugated to a Multivalent Carbohydrate Cluster for Cellular Targeting

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• 作者：Martin A. Maier ; Constantin G. Yannopoulos ; Nazim Mohamed ; Arlene Roland ; Hans Fritz ; V. Mohan ; George Just ; and Muthiah Manoharan
• 刊名：Bioconjugate Chemistry
• 出版年：2003
• 出版时间：January 2003
• 年：2003
• 卷：14
• 期：1
• 页码：18 - 29
• 全文大小：221K
• 年卷期：v.14,no.1(January 2003)
• ISSN：1520-4812

文摘

Carrier-mediated delivery holds great promise for significantly improving the cellular uptake andtherefore the therapeutic efficacy of antisense oligonucleotides in vivo. A multivalent carbohydraterecognition motif for the asialoglycoprotein receptor has been designed for tissue- and cell-specificdelivery of antisense drugs to parenchymal liver cells. To combine low molecular weight with highreceptor affinity, the synthetic ligand contains three galactosyl residues attached to a cholane scaffoldvia ges/gifchars/epsilon.gif" BORDER=0 >-aminocapramide linkers. Three-dimensional structural calculations indicate that this uniquedesign provides proper spacing and orientation of the three galactosyl residues to accomplish highaffinity binding to the receptor. Covalent conjugation of the bulky carbohydrate cluster to oligonucleotides has been achieved by solid-phase synthesis using low-loaded macroporous resins and optimizedsynthesis protocols.