RNA interference using boranophosphate siRNAs: structure-activity relationships
RNA interference using boranophosphate siRNAs: structure-activity relationships
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DOI：
10.1093/nar/gkh936
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发表时间：
2004-01-01
影响因子：
14.9
通讯作者：
Alexander, KA
中科院分区：
文献类型：
--
作者：
Hall, AHS;Wan, J;Alexander, KA
在RNA干扰（RNAi）中，短的双链RNA（称为siRNA）抑制同源基因的表达。由于细胞内和细胞外核酸酶的普遍存在，siRNA的临床或临床前使用可能需要稳定化修饰。为了检测修饰对siRNA功效和稳定性的影响，我们开发了一种合成有规立构的硼烷基磷酸siRNA的新方法。这项工作表明，硼磷酸siRNA始终比广泛使用的硫代磷酸酯修饰的siRNA更有效。此外，如果反义链的中心未被修饰，硼磷酸siRNA通常比天然siRNA更有活性。硼磷酸修饰也增加siRNA效力。硼磷酸siRNA比未修饰的siRNA具有至少10倍的核酸酶抗性，这一发现可以解释硼磷酸修饰的一些积极作用。硼磷酸siRNA的生物化学性质使它们成为基于RNAi的治疗剂的有希望的候选者。
In RNA interference (RNAi), short double-stranded RNA (known as siRNA) inhibits expression from homologous genes. Clinical or pre-clinical use of siRNAs is likely to require stabilizing modifications because of the prevalence of intracellular and extracellular nucleases. In order to examine the effect of modification on siRNA efficacy and stability, we developed a new method for synthesizing stereoregular boranophosphate siRNAs. This work demonstrates that boranophosphate siRNAs are consistently more effective than siRNAs with the widely used phosphorothioate modification. Furthermore, boranophosphate siRNAs are frequently more active than native siRNA if the center of the antisense strand is not modified. Boranophosphate modification also increases siRNA potency. The finding that boranophosphate siRNAs are at least ten times more nuclease resistant than unmodified siRNAs may explain some of the positive effects of boranophosphate modification. The biochemical properties of boranophosphate siRNAs make them promising candidates for an RNAi-based therapeutic.