Effect of modular conjugation strategy for N-acetylgalactosamine-targeted antisense oligonucleotides.

Effect of modular conjugation strategy for N-acetylgalactosamine-targeted antisense oligonucleotides. Nucleosides Nucleotides Nucleic Acids. 2019 Oct 16;:1-10 Authors: Yamamoto T, Sawamura M, Terada C, Kashiwada K, Wada F, Yamayoshi A, Obika S, Harada-Shiba M Abstract The asialoglycoprotein receptor (ASGPr) and N-acetylgalactosamine (GalNAc) is one of the most reliable receptor-ligand combinations for delivering antisense oligonucleotides (ASOs) to the liver. Here, we show that a modular GalNAc conjugation strategy allows us to reinforce the activity of the parent, naked 2',4'-BNA/LNA gapmer targeting apolipoprotein B. The conjugation partly reduced a possible hepatotoxicity of the parent ASO. The structure-activity study revealed the significance of the metabolic susceptibility of the GalNAc moiety to nucleolytic cleavage that results in exposure of the parent gapmer. The broad usefulness of our delivery strategy of ASOs to the liver has been demonstrated. PMID: 31617782 [PubMed - as supplied by publisher]
Source: Nucleosides, Nucleotides and Nucleic Acids - Category: Biochemistry Tags: Nucleosides Nucleotides Nucleic Acids Source Type: research