Phosphorothioate modified oligonucleotide-protein interactions
Phosphorothioate modified oligonucleotide-protein interactions
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DOI：
10.1093/nar/gkaa299
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发表时间：
2020-06-04
影响因子：
14.9
通讯作者：
Liang, Xue-hai
中科院分区：
文献类型：
--
作者：
Crooke, Stanley T.;Vickers, Timothy A.;Liang, Xue-hai
反义寡核苷酸（Antisense oligonucleotides，ASO）通过与靶RNA杂交，通过不同的机制调控基因表达。阿索治疗剂是化学修饰的，并且包括硫代磷酸酯（PS）骨架修饰和不同的核糖和碱基修饰以改善药理学性质。修饰的PS ASO显示出对靶RNA更好的结合亲和力和增加的对蛋白质的结合。此外，PS阿索蛋白相互作用可影响其性能的许多方面，包括分布和组织递送、细胞摄取、细胞内运输、效力和毒性。本文综述了近年来对PS阿索蛋白相互作用的研究进展，重点介绍了与PS ASO相互作用的蛋白、PS阿索蛋白相互作用对阿索性能的影响以及PS阿索修饰与蛋白相互作用的构效关系。对这些相互作用的详细了解可以帮助设计更安全和更有效的阿索药物，正如最近的研究结果所示，改变阿索化学修饰可以显着提高治疗指数。
Antisense oligonucleotides (ASOs) interact with target RNAs via hybridization to modulate gene expression through different mechanisms. ASO therapeutics are chemically modified and include phosphorothioate (PS) backbone modifications and different ribose and base modifications to improve pharmacological properties. Modified PS ASOs display better binding affinity to the target RNAs and increased binding to proteins. Moreover, PS ASO protein interactions can affect many aspects of their performance, including distribution and tissue delivery, cellular uptake, intracellular trafficking, potency and toxicity. In this review, we summarize recent progress in understanding PS ASO protein interactions, highlighting the proteins with which PS ASOs interact, the influence of PS ASO protein interactions on ASO performance, and the structure activity relationships of PS ASO modification and protein interactions. A detailed understanding of these interactions can aid in the design of safer and more potent ASO drugs, as illustrated by recent findings that altering ASO chemical modifications dramatically improves therapeutic index.