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.

中文翻译：

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模块化缀合策略对 N-乙酰半乳糖胺靶向反义寡核苷酸的影响

摘要 去唾液酸糖蛋白受体 (ASGPr) 和 N-乙酰半乳糖胺 (GalNAc) 是将反义寡核苷酸 (ASO) 输送到肝脏的最可靠的受体-配体组合之一。在这里，我们展示了模块化 GalNAc 结合策略使我们能够增强亲本的活性，裸 2',4'-BNA/LNA gapmer 靶向载脂蛋白 B。该结合部分降低了亲本 ASO 可能的肝毒性。构效研究揭示了 GalNAc 部分对导致母体 gapmer 暴露的核酸裂解的代谢敏感性的重要性。已经证明了我们将 ASO 递送到肝脏的策略的广泛用途。