Peel Brandon J, Hagen Gordon, Krishnamurthy Kalaivani, Desaulniers Jean-Paul
University of Ontario Institute of Technology , Faculty of Science, 2000 Simcoe Street North, Oshawa, Ontario L1H 7K4, Canada.
ACS Med Chem Lett. 2014 Dec 4;6(2):117-22. doi: 10.1021/ml500260j. eCollection 2015 Feb 12.
Short interfering RNAs (siRNAs) have tremendous potential as a new class of next-generation therapeutics; however, their progress is lagging due to issues related to stability, biodistribution, and cell-membrane permeability. To overcome these issues, there is widespread interest in chemically modifying siRNAs. In this study, siRNAs that contain a triazole-backbone unit with pyrimidine-modified hydrophobic substituents were synthesized and examined for their gene-silencing activity. In our study, we generated a library of siRNAs that target both a plasmid reporter system and an endogenous gene target, bcl-2. Our results indicate that these unique modifications are well tolerated within the RNA interference pathway. In addition, a cholesterol-modified triazole-linked siRNA targeting the exogenous target firefly luciferase was capable of gene-silencing at levels greater than 80% in the absence of a carrier complex.
短干扰RNA（siRNA）作为一类新型的下一代治疗药物具有巨大潜力；然而，由于与稳定性、生物分布和细胞膜通透性相关的问题，其进展滞后。为克服这些问题，人们对化学修饰siRNA有着广泛的兴趣。在本研究中，合成了含有带有嘧啶修饰疏水取代基的三唑主链单元的siRNA，并检测了它们的基因沉默活性。在我们的研究中，我们构建了一个靶向质粒报告系统和内源性基因靶点bcl-2的siRNA文库。我们的结果表明，这些独特的修饰在RNA干扰途径中具有良好的耐受性。此外，一种靶向外源靶点萤火虫荧光素酶的胆固醇修饰的三唑连接siRNA在没有载体复合物的情况下能够实现大于80%水平的基因沉默。
