Site-specific Incorporation of 2′,5′-Linked Nucleic Acids Enhances Therapeutic Profile of Antisense Oligonucleotides
Site-specific Incorporation of 2′,5′-Linked Nucleic Acids Enhances Therapeutic Profile of Antisense Oligonucleotides
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DOI：
10.1021/acsmedchemlett.1c00072
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发表时间：
2021-04-05
影响因子：
4.2
通讯作者：
Seth, Punit P.
中科院分区：
文献类型：
--
作者：
Prakash, Thazha P.;Yu, Jinghua;Seth, Punit P.
在毒性硫代磷酸酯（PS）缺口聚物ASO的脱氧核苷酸缺口区域中位点特异性掺入2 '-修饰和中性键可以增强治疗指数和安全性。在本手稿中，我们确定了在脱氧核苷酸缺口区域中引入2 '，5'-连接的RNA对PS ASO的毒性和效力的影响。我们的结果表明，在差距区域中掺入2 '，5'-连接的RNA显著改善了PS-ASO的肝毒性特征而不损害效力，并提供了用于改善阿索药物的治疗指数的新的替代化学方法。
Site-specific incorporation of 2'-modifications and neutral linkages in the deoxynucleotide gap region of toxic phosphorothioate (PS) gapmer ASOs can enhance therapeutic index and safety. In this manuscript, we determined the effect of introducing 2',5'-linked RNA in the deoxynucleotide gap region on toxicity and potency of PS ASOs. Our results demonstrate that incorporation of 2',5'-linked RNA in the gap region dramatically improved hepatotoxicity profile of PS-ASOs without compromising potency and provide a novel alternate chemical approach for improving therapeutic index of ASO drugs.