2. Academic Validation
  3. Synthesis of 5'-GalNAc-Conjugated Oligonucleotides: A Comparison of Solid and Solution-Phase Conjugation Strategies

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

  • Molecules. 2017 Aug 15;22(8):1356. doi: 10.3390/molecules22081356.
Isaiah Cedillo 1,  Dana Chreng 2,  Elyse Engle 3,  Lijian Chen 4,  Andrew K McPherson 5,  Andrew A Rodriguez 6
Affiliations

Affiliations

  • 1 Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA. ICedillo@ionisph.com.
  • 2 Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA. dchreng@ionisph.com.
  • 3 Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA. eengle@ionisph.com.
  • 4 Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA. lchen@ionisph.com.
  • 5 Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA. amcpherson@ionisph.com.
  • 6 Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA. Arodriguez@ionisph.com.
PMID: 28809818 DOI: 10.3390/molecules22081356
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.

Keywords

GalNAc; conjugate; oligonucleotide.

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