Serial incorporation of a monovalent GalNAc phosphoramidite unit into hepatocyte-targeting antisense oligonucleotides

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• 作者：Tsuyoshi Yamamoto^a ; ^b ; ^{t-yam@phs.osaka-u.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Motoki Sawamura^a ; ^b ; Fumito Wada^a ; ^b ; Mariko Harada-Shiba^a ; Satoshi Obika^b ; ^{obika@phs.osaka-u.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Antisense oligonucleotides ; GalNAc ; Asialoglycoprotein receptors ; Bio-labile linker ; Bridged nucleic acid ; Locked nucleic acid ; Apolipoproteins ; Hypercholesterolemia
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 January 2016
• 年：2016
• 卷：24
• 期：1
• 页码：26-32
• 全文大小：936 K

文摘

The targeting of abundant hepatic asialoglycoprotein receptors (ASGPR) with trivalent N-acetylgalactosamine (GalNAc) is a reliable strategy for efficiently delivering antisense oligonucleotides (ASOs) to the liver. We here experimentally demonstrate the high systemic potential of the synthetically-accessible, phosphodiester-linked monovalent GalNAc unit when tethered to the 5′-terminus of well-characterised 2′,4′-bridged nucleic acid (also known as locked nucleic acid)-modified apolipoprotein B-targeting ASO via a bio-labile linker. Quantitative analysis of the hepatic disposition of the ASOs revealed that phosphodiester is preferable to phosphorothioate as an interunit linkage in terms of ASGPR binding of the GalNAc moiety, as well as the subcellular behavior of the ASO. The flexibility of this monomeric unit was demonstrated by attaching up to 5 GalNAc units in a serial manner and showing that knockdown activity improves as the number of GalNAc units increases. Our study suggests the structural requirements for efficient hepatocellular targeting using monovalent GalNAc and could contribute to a new molecular design for suitably modifying ASO.