Solid-phase synthesis of 5'-triantennary N-acetylgalactosamine conjugated antisense oligonucleotides using phosphoramidite chemistry

Bioorg Med Chem Lett. 2015 Oct 1;25(19):4127-30. doi: 10.1016/j.bmcl.2015.08.019. Epub 2015 Aug 8.

Abstract

A convenient solid-phase synthetic method was developed for assembling a triantennary N-acetylgalactosamine (GalNAc) cluster on the 5'-end of antisense oligonucleotide using phosphoramidite chemistry. Conjugation of the 5'-triantennary GalNAc cluster improved potency of the 14 mer ASO 7-fold in mice and more than 50 fold in hepatocytes. The synthetic approach described in this Letter simplifies the synthesis of 5'-triantennary GalNAc cluster conjugated ASOs and helps understand the structure-activity relationship for targeting hepatocytes with oligonucleotide therapeutics.

Keywords: (S)-cEt BNA ASO; 5′-PGalNAc(3); GalNAc conjugation; Hepatocyte targeted delivery.

MeSH terms

  • Acetylgalactosamine / analogs & derivatives*
  • Acetylgalactosamine / chemistry*
  • Animals
  • Dose-Response Relationship, Drug
  • Liver / metabolism
  • Mice
  • Oligonucleotides, Antisense / chemical synthesis*
  • Oligonucleotides, Antisense / chemistry*
  • Organophosphorus Compounds / chemistry*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Scavenger Receptors, Class B / antagonists & inhibitors*
  • Scavenger Receptors, Class B / metabolism
  • Structure-Activity Relationship

Substances

  • Oligonucleotides, Antisense
  • Organophosphorus Compounds
  • RNA, Messenger
  • Scarb1 protein, mouse
  • Scavenger Receptors, Class B
  • phosphoramidite
  • Acetylgalactosamine