Solid-phase synthesis of 5′-triantennary N-acetylgalactosamine conjugated antisense oligonucleotides using phosphoramidite chemistry. Issue 19 (1st October 2015)

• Record Type: Journal Article
• Authors: Prakash, Thazha P.; Brad Wan, W.; Low, Audrey; Yu, Jinghua; Chappell, Alfred E.; Gaus, Hans; Kinberger, Garth A.; Østergaard, Michael E.; Migawa, Michael T.; Swayze, Eric E.; Seth, Punit P.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 19(2015)
• Page Start: 4127
• Page End: 4130
• Publication Date: 2015-10-01
• Subjects: 5′-PGalNAc3 -- GalNAc conjugation -- Hepatocyte targeted delivery -- (S)-cEt BNA ASO; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.08.019
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.