Chemical modification resolves the asymmetry of siRNA strand degradation in human blood serum
Chemical modification resolves the asymmetry of siRNA strand degradation in human blood serum
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DOI：
10.1261/rna.602307
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发表时间：
2007-11-01
期刊：
影响因子：
4.5
通讯作者：
Walter, Nils G.
中科院分区：
文献类型：
--
作者：
Hoerter, John A. H.;Walter, Nils G.
小干扰（si）RNA最近已被用于在静脉内全身递送后在体内治疗性沉默基因。siRNA治疗剂开发的进一步进展将部分依赖于定制siRNA的位点特异性化学修饰以优化其药代动力学性质。特别需要改进这些双链RNA药物在体内的溶核稳定性并抑制不利的脱靶基因沉默效应。在这里，我们证明了特定的化学2 '-O-甲基化，这已经被证明可以改善siRNA的无处不在的脱靶毒性，选择性地保护引导链的特别脆弱的5'端免受人血清中的核酸外切降解。因此，特定的化学修饰解决了引导链和随从链的不对称降解，这是siRNA末端的热力学不对称所固有的，这是在RNA干扰中正确利用引导链所需的。
Small interfering ( si) RNAs have recently been used to therapeutically silence genes in vivo after intravenous systemic delivery. Further progress in the development of siRNA therapeutics will in part rely on tailoring site-specific chemical modifications of siRNAs to optimize their pharmacokinetic properties. Advances are particularly needed to improve the nucleolytic stability of these double-stranded RNA drugs in vivo and suppress adverse off-target gene silencing effects. Here we demonstrate that specific chemical 2'-O-methylation, which has already been shown to ameliorate the omnipresent off-target toxicity of siRNAs, selectively protects the particularly vulnerable 5'-end of the guide strand against exonucleolytic degradation in human blood serum. Specific chemical modification thus resolves the asymmetric degradation of the guide and passenger strands, which is inherent to the thermodynamic asymmetry of the siRNA termini as required for proper utilization of the guide strand in RNA interference.