Faculty of Science, University of Ontario Institute of Technology, Oshawa, Ontario, Canada.
Bioorg Med Chem Lett. 2012 Feb 15;22(4):1722-6. doi: 10.1016/j.bmcl.2011.12.104. Epub 2011 Dec 30.
An efficient synthesis of siRNAs modified at the backbone with a triazole functionality is reported. Through the use of 4,4'-dimethoxytrityl (DMT) phosphoramidite chemistry, triazole backbone dimers were site-specifically incorporated throughout various siRNAs targeting both firefly luciferase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene transcripts as representatives of an exogenous and endogenous gene, respectively. Following the successful silencing of the firefly luciferase reporter gene, triazole-modified siRNAs were also found to be capable of silencing GAPDH in a dose-dependent manner. Backbone modifications approaching the 3'-end on the sense strand were tolerated without compromising siRNA potency. This study highlights the compatibility of triazole-modified siRNAs within the RNAi pathway, and the modification's potential to impart favorable properties to siRNAs designed to target other endogenous genes.
报道了一种在骨架上带有三唑官能团的 siRNA 的高效合成方法。通过使用 4,4'-二甲氧基三苯甲基 (DMT) 亚磷酰胺化学，三唑骨架二聚体被特异性地掺入到针对萤火虫荧光素酶和甘油醛-3-磷酸脱氢酶 (GAPDH) 基因转录本的各种 siRNA 中，分别作为外源和内源性基因的代表。在成功沉默萤火虫荧光素酶报告基因后，还发现三唑修饰的 siRNA 能够以剂量依赖的方式沉默 GAPDH。在不影响 siRNA 效力的情况下，在有义链的 3'-末端附近进行骨架修饰是可以容忍的。这项研究强调了三唑修饰的 siRNA 在 RNAi 途径中的兼容性，以及修饰赋予针对其他内源性基因设计的 siRNA 有利特性的潜力。
