从晶体结构角度深入探讨 3'-氟己糖核酸的 S-和 R-6'-甲基主链修饰对 RNA 亲和力的相反影响。
Insights from crystal structures into the opposite effects on RNA affinity caused by the S- and R-6'-methyl backbone modifications of 3'-fluoro hexitol nucleic acid.
机构信息
Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States.
出版信息
Biochemistry. 2012 Jan 10;51(1):7-9. doi: 10.1021/bi201810r. Epub 2011 Dec 29.
Abstract
Locked nucleic acid (LNA) analogues with 2',4'-bridged sugars show promise in antisense applications. S-5'-Me-LNA has high RNA affinity, and modified oligonucleotides show weakened immune stimulation in vivo. Conversely, an R-5'-methyl group dramatically lowers RNA affinity. To test the effects of S- and R-6'-methyl groups on 3'-fluoro hexitol nucleic acid (FHNA) stability, we synthesized S- and R-6'-Me-FHNA thymidine and incorporated them into oligo-2'-deoxynucleotides. As with LNA, S-6'-Me is stabilizing whereas R-6'-Me is destabilizing. Crystal structures of 6'-Me-FHNA-modified DNAs explain the divergent consequences for stability and suggest convergent origins of these effects by S- and R-6'-Me (FHNA) [-5'-Me (LNA and RNA)] substituents.
摘要
锁核酸（LNA）类似物具有 2'，4'-桥接的糖，在反义应用中具有很大的前景。S-5'-Me-LNA 具有高的 RNA 亲和力，并且修饰的寡核苷酸在体内显示出减弱的免疫刺激作用。相反，R-5'-甲基基团大大降低了 RNA 的亲和力。为了测试 S-和 R-6'-甲基对 3'-氟己糖醇核酸（FHNA）稳定性的影响，我们合成了 S-和 R-6'-Me-FHNA 胸腺嘧啶，并将其掺入到寡脱氧核苷酸中。与 LNA 一样，S-6'-Me 是稳定的，而 R-6'-Me 是不稳定的。6'-Me-FHNA 修饰的 DNA 的晶体结构解释了稳定性的不同结果，并通过 S-和 R-6'-Me（FHNA）[-5'-Me（LNA 和 RNA）]取代基提出了这些效应的趋同起源。
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