Efficient Synthesis and Biological Evaluation of 5鈥?GalNAc Conjugated Antisense Oligonucleotides

详细信息    查看全文

• 作者：Michael E. 脴stergaard ; Jinghua Yu ; Garth A. Kinberger ; W. Brad Wan ; Michael T. Migawa ; Guillermo Vasquez ; Karsten Schmidt ; Hans J. Gaus ; Heather M. Murray ; Audrey Low ; Eric E. Swayze ; Thazha P. Prakash ; Punit P. Seth
• 刊名：Bioconjugate Chemistry
• 出版年：2015
• 出版时间：August 19, 2015
• 年：2015
• 卷：26
• 期：8
• 页码：1451-1455
• 全文大小：354K
• ISSN：1520-4812

文摘

Conjugation of triantennary N-acetyl galactosamine (GalNAc) to oligonucleotide therapeutics results in marked improvement in potency for reducing gene targets expressed in hepatocytes. In this report we describe a robust and efficient solution-phase conjugation strategy to attach triantennary GalNAc clusters (mol. wt. 鈭?000) activated as PFP (pentafluorophenyl) esters onto 5鈥?hexylamino modified antisense oligonucleotides (5鈥?HA ASOs, mol. wt. 鈭?000 Da). The conjugation reaction is efficient and was used to prepare GalNAc conjugated ASOs from milligram to multigram scale. The solution phase method avoids loading of GalNAc clusters onto solid-support for automated synthesis and will facilitate evaluation of GalNAc clusters for structure activity relationship (SAR) studies. Furthermore, we show that transfer of the GalNAc cluster from the 3鈥?end of an ASO to the 5鈥?end results in improved potency in cells and animals.