Effect of modular conjugation strategy for N-acetylgalactosamine-targeted antisense oligonucleotides
Effect of modular conjugation strategy for N-acetylgalactosamine-targeted antisense oligonucleotides
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DOI：
10.1080/15257770.2019.1677911
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发表时间：
2020-02
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通讯作者：
Tsuyoshi Yamamoto;Motoki Sawamura;Chisato Terada;Koki Kashiwada;Fumito Wada;A. Yamayoshi;S. Obika;M. Harada‐Shiba
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文献类型：
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作者：
Tsuyoshi Yamamoto;Motoki Sawamura;Chisato Terada;Koki Kashiwada;Fumito Wada;A. Yamayoshi;S. Obika;M. Harada‐Shiba
摘要 脱唾液酸糖蛋白受体 (ASGPr) 和 N-乙酰半乳糖胺 (GalNAc) 是将反义寡核苷酸 (ASO) 递送至肝脏的最可靠的受体-配体组合之一。在这里，我们展示了模块化的 GalNAc 缀合策略使我们能够增强亲本、裸露 2',4'-BNA/LNA gapmer 靶向载脂蛋白 B 的活性。这种缀合部分减少了亲本 ASO 可能的肝毒性。结构-活性研究揭示了 GalNAc 部分对导致母体间隙体暴露的溶核切割的代谢敏感性的重要性。我们的 ASO 肝脏递送策略的广泛用途已得到证实。
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.