Facile Synthesis, Geometry, and 2′-Substituent-Dependent in Vivo Activity of 5′-(E)- and 5′-(Z)-Vinylphosphonate-Modified siRNA Conjugates,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Facile Synthesis, Geometry, and 2′-Substituent-Dependent in Vivo Activity of 5′-(E)- and 5′-(Z)-Vinylphosphonate-Modified siRNA Conjugates
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-01-27 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01147
Rubina Giare Parmar ₁ , Christopher R. Brown ₁ , Shigeo Matsuda ₁ , Jennifer L. S. Willoughby ₁ , Christopher S. Theile ₁ , Klaus Charissé ₁ , Donald J. Foster ₁ , Ivan Zlatev ₁ , Vasant Jadhav ₁ , Martin A. Maier ₁ , Martin Egli ₂ , Muthiah Manoharan ₁ , Kallanthottathil G. Rajeev ₁

Affiliation

(E)-Vinylphosphonate ((E)-VP), a metabolically stable phosphate mimic at the 5′-end of the antisense strand, enhances the in vivo potency of siRNA. Here we describe a straightforward synthetic approach to incorporate a nucleotide carrying a vinylphosphonate (VP) moiety at the 5′-end of oligonucleotides under standard solid-phase synthesis and deprotection conditions by utilizing pivaloyloxymethyl (POM) protected VP-nucleoside phosphoramidites. The POM protection enhances scope and scalability of 5′-VP-modified oligonucleotides and, in a broader sense, the synthesis of oligonucleotides modified with phosphonate moieties. Trivalent N-acetylgalactosamine-conjugated small interfering RNA (GalNAc-siRNA) comprising (E)-geometrical isomer of VP showed improved RISC loading with robust RNAi-mediated gene silencing in mice compared to the corresponding (Z)-isomer despite similar tissue accumulation. We also obtained structural insights into why bulkier 2′-ribosugar substitutions such as 2′-O-[2-(methylamino)-2-oxoethyl] are well tolerated only when combined with 5′-(E)-VP.

中文翻译：

5'-（E）-和5'-（Z）-乙烯基膦酸酯修饰的siRNA的体内合成的简便合成，几何形状和2'-取代基的体内活性

（E）-乙烯基膦酸酯（（E）-VP）是一种在反义链5'端具有代谢稳定性的磷酸盐模拟物，可增强siRNA的体内效力。在这里，我们描述了一种简单的合成方法，通过利用新戊酰氧基甲基（POM）保护的VP-核苷亚磷酰胺，在标准固相合成和脱保护条件下并入在寡核苷酸的5'-末端带有乙烯基膦酸酯（VP）部分的核苷酸。POM保护提高了5'-VP修饰的寡核苷酸的范围和可扩展性，并且从更广泛的意义上说，增强了用膦酸酯部分修饰的寡核苷酸的合成。三价N-乙酰半乳糖胺缀合的小干扰RNA（GalNAc-siRNA），包含（E与类似的（Z）异构体相比，VP的几何异构体在小鼠中具有强大的RNAi介导的基因沉默，从而改善了RISC装载，尽管组织积累相似。我们还获得了结构上的见解，以了解为什么只有与5'-（E）-VP结合才能很好地耐受较大的2'-核糖替代品，例如2'- O- [2-（甲基氨基）-2-氧代乙基] 。

更新日期：2018-01-27

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南