title: Solid-phase synthesis of 5'-triantennary N-acetylgalactosamine conjugated antisense oligonucleotides using phosphoramidite chemistry.
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.
authors: Medicinal Chemistry, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States. Electronic address: tprakash@isisph.com.
authors: Thazha P
authors: TP
authors: Prakash
authors: Medicinal Chemistry, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors: W
authors: W
authors: Brad Wan
authors: Medicinal Chemistry, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors: Audrey
authors: A
authors: Low
authors: Medicinal Chemistry, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors: Jinghua
authors: J
authors: Yu
authors: Medicinal Chemistry, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors: Alfred E
authors: AE
authors: Chappell
authors: Medicinal Chemistry, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors: Hans
authors: H
authors: Gaus
authors: Medicinal Chemistry, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors: Garth A
authors: GA
authors: Kinberger
authors: Medicinal Chemistry, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors: Michael E
authors: ME
authors: Østergaard
authors: Medicinal Chemistry, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors: Michael T
authors: MT
authors: Migawa
authors: Medicinal Chemistry, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors: Eric E
authors: EE
authors: Swayze
authors: Medicinal Chemistry, Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, United States.
authors: Punit P
authors: PP
authors: Seth
mesh_terms: D000116:Acetylgalactosamine / Q000031:analogs & derivatives* / Q000737:chemistry*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000378:metabolism; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis* / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000737:chemistry*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D016376:Oligonucleotides, Antisense; D009943:Organophosphorus Compounds; D012333:RNA, Messenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C434331:phosphoramidite; D000116:Acetylgalactosamine
keywords: (S)-cEt BNA ASO; 5′-PGalNAc(3); GalNAc conjugation; Hepatocyte targeted delivery