Synthesis of multivalent fatty acid-conjugated antisense oligonucleotides: Cell internalization, physical properties, and in vitro and in vivo activities
Synthesis of multivalent fatty acid-conjugated antisense oligonucleotides: Cell internalization, physical properties, and in vitro and in vivo activities
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多价脂肪酸缀合反义寡核苷酸的合成：细胞内化、物理特性以及体外和体内活性
DOI：
10.1016/j.bmc.2023.117192
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发表时间：
2023
影响因子：
3.5
通讯作者：
Obika Satoshi
中科院分区：
文献类型：
--
作者：
Tanaka Yuya;Tanioku Yurika;Nakayama Taisuke;Aso Kotomi;Yamaguchi Takao;Kamada Haruhiko;Obika Satoshi
在此，我们描述了多缀合脂肪酸单体亚磷酰胺的设计和合成及其与反义寡核苷酸（ASO）的缀合。多价长链脂肪酸结合提高了细胞对ASO的摄取，但由于物理性质和细胞定位的改变，降低了体外活性。此外，在体内实验中，多价脂肪酸结合的ASO与未结合的阿索相比表现出不同的器官特异性。尽管可能需要优化脂肪酸部分和阿索之间的接头结构，但二价长链脂肪酸缀合提供了增加内吞作用的新方法，从而潜在地改善治疗性ASO的活性。
Herein, we describe the design and synthesis of multi-conjugatable fatty acid monomer phosphoramidites and their conjugation to antisense oligonucleotides (ASOs). Multivalent long-chain fatty acid conjugation improved the cellular uptake of ASOs but decreasedin vitroactivity due to alterations in physical properties and cellular localization. In addition, multivalently fatty acid-conjugated ASOs showed different organ specificity compared with that of unconjugated ASO inin vivoexperiment. Although optimization of the linker structure between the fatty acid moiety and the ASO may be required, divalent long-chain fatty acid conjugation provides a new approach to increase endocytosis, thereby potentially improving the activity of therapeutic ASOs.