Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
Molecules. 2017 Aug 15;22(8):1356. doi: 10.3390/molecules22081356.
Antisense oligonucleotides (ASOs) conjugated to triantennary -acetyl galactosamine (GalNAc) ligands represent an emerging approach to antisense therapy. Our current generation of GalNAc-ASO conjugates link the GalNAc to the 5'-terminus of the ASO. The conjugation reaction can be accomplished using solution-phase or solid-phase techniques. Here we show a direct comparison of a solution-phase and a solid-phase conjugation strategy. The solution-phase approach, using amine-pentafluorophenyl (PFP) ester coupling, is higher yielding and gives material of slightly higher purity, but requires several additional unit operations and longer production time. The solid-phase approach, using a protected GalNAc ligand phosphoramidite, is more expedient, but results in lower yield and purity. Both strategies efficiently deliver conjugated material in excellent purity.
反义寡核苷酸（ASOs）与三触角乙酰半乳糖胺（GalNAc）配体缀合代表了反义治疗的一种新兴方法。我们当前一代的 GalNAc-ASO 缀合物将 GalNAc 连接到 ASO 的 5'末端。缀合反应可以使用溶液相或固相技术来完成。在这里，我们展示了溶液相和固相缀合策略的直接比较。使用胺-五氟苯基（PFP）酯偶联的溶液相方法产率更高，得到的产物纯度略高，但需要更多的单元操作和更长的生产时间。使用保护的 GalNAc 配体磷酰胺的固相方法更方便，但产率和纯度较低。这两种策略都能以优异的纯度有效地输送缀合材料。
