含有 C5-丙炔基修饰的阿拉伯糖核酸与 RNA 形成稳定的杂交双链体，可被大肠杆菌 RNase H 有效降解。

Arabinonucleic acids containing C5-propynyl modifications form stable hybrid duplexes with RNA that are efficiently degraded by E. coli RNase H.

机构信息

Department of Chemistry and Biochemistry, Faculty of Arts and Science, Concordia University, 7141 Rue Sherbrooke Ouest, Montréal, Québec H4B 1R6, Canada.

出版信息

Bioorg Med Chem Lett. 2022 Jul 1;67:128744. doi: 10.1016/j.bmcl.2022.128744. Epub 2022 Apr 19.

DOI:10.1016/j.bmcl.2022.128744

PMID:35452799

Abstract

The promise of the antisense approach to treat a variety of diseases with oligonucleotides and solutions to challenges that have been encountered in their development is attributable to chemical modification of the nucleic acid scaffold. Herein, we describe preliminary data regarding the synthesis of a novel C5-propynyl-β-d-arabinouridine (araU) phosphoramidite and its incorporation into oligonucleotides. Substitution of araU in dT results in minor stabilization of duplexes formed with RNA when modifications are placed consecutively and a uniformly modified araU 18-mer increases stability by 34 °C relative to DNA. The modified oligomer exhibits improved nuclease and serum stability when compared to DNA and duplexes formed between RNA and araU oligonucleotides are substrates for E. coli RNase H. These preliminary results merit further investigation into C5-propynyl modified arabino nucleic acids for potential therapeutic gene silencing applications.

摘要

反义技术有望通过寡核苷酸治疗多种疾病，并且通过对核酸支架进行化学修饰，解决了在其发展过程中遇到的挑战。在此，我们描述了一种新型 C5-丙炔基-β-d-阿拉伯呋喃糖基（araU）亚磷酰胺的合成及其在寡核苷酸中的掺入的初步数据。当修饰物连续放置时，用 araU 替代 dT 会导致与 RNA 形成的双链体略微稳定，并且相对于 DNA，均一地修饰的 araU18-mer 将稳定性提高了 34°C。与 DNA 相比，修饰的寡聚物具有更好的核酸酶和血清稳定性，并且在 araU 寡核苷酸之间形成的双链体是大肠杆菌 RNase H 的底物。这些初步结果值得进一步研究 C5-丙炔基修饰的阿拉伯糖核酸在潜在的治疗性基因沉默应用中的价值。