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Molecules 2017, 22(8), 1356; doi:10.3390/molecules22081356

Synthesis of 5′-GalNAc-Conjugated Oligonucleotides: A Comparison of Solid and Solution-Phase Conjugation Strategies

Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
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Received: 11 July 2017 / Revised: 7 August 2017 / Accepted: 10 August 2017 / Published: 15 August 2017
(This article belongs to the Special Issue Synthesis and Applications of Oligonucleotide Conjugates)
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Abstract

Antisense oligonucleotides (ASOs) conjugated to triantennary N-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. View Full-Text
Keywords: oligonucleotide; GalNAc; conjugate oligonucleotide; GalNAc; conjugate
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Cedillo, I.; Chreng, D.; Engle, E.; Chen, L.; McPherson, A.K.; Rodriguez, A.A. Synthesis of 5′-GalNAc-Conjugated Oligonucleotides: A Comparison of Solid and Solution-Phase Conjugation Strategies. Molecules 2017, 22, 1356.

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