Amides as excellent mimics of phosphate linkages in RNA.
Amides as excellent mimics of phosphate linkages in RNA.
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DOI：
10.1002/anie.201007012
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发表时间：
2011-02-25
影响因子：
16.6
通讯作者：
Rozners, Eriks
中科院分区：
文献类型：
--
作者：
Selvam, Chelliah;Thomas, Siji;Abbott, Jason;Kennedy, Scott D.;Rozners, Eriks
自从发现RNA可以催化化学反应后，非编码RNA的数量和种类及其在生物学中的重要作用一直在稳步增长。骨架修饰的RNA可以在基础生物学和非编码RNA的生物医学中得到广泛的应用，前提是这些修饰模仿了磷酸二酯键的结构，并且不改变RNA的构象。特别是，RNA干扰(RNAi)成为一种新的治疗策略的潜力重新燃起了人们对化学修饰的兴趣，这些化学修饰可能会优化短干扰RNA(SiRNAs)的药理学特性。[1]我们对磷酸骨架的疏水性非离子模拟物感兴趣，如甲醛[2]和酰胺[3]，它们可能赋予对siRNAs高核酸酶抗性，同时减少电荷和增加疏水性。早期的工作表明，3-CH2-CO-NH-5核苷酰胺键(这里简称AM1)在A型DNA-RNA异源双链的DNA链中具有很好的耐受性。[4]随后，我们发现AM1的修饰并没有改变RNA-RNA双链的热稳定性。[3]最重要的是，Iwase和他的同事[5]最近表明AM1酰胺在siRNA的3-悬臂中具有很好的耐受性。综合这些数据表明，酰胺可能是RNA中磷酸键的很好的模拟，然而，除了简单的熔融温度测量之外，酰胺修饰的RNA的结构和热力学性质还没有建立。在这里，我们提出了第一个全面的结构和热力学研究，清楚地表明AM1键不会干扰RNA的A型结构、热稳定性和水化作用
After the discovery that RNA can catalyze chemical reactions, the number and variety of non-coding RNAs and the important roles they play in biology has been growing steadily. Backbone modified RNA may find broad applications in fundamental biology and biomedicine of non-coding RNAs, providing that the modifications mimic the structure of the phosphodiester linkage and do not alter the conformation of RNA. In particular, the potential of RNA interference (RNAi) to become a new therapeutic strategy has revitalized interest in chemical modifications that may optimize the pharmacological properties of short interfering RNAs (siRNAs).[1] We are interested in hydrophobic non-ionic mimics of the phosphate backbone, such as formacetals [2] and amides [3], that may confer high nuclease resistance to siRNAs along with reduced charge and increased hydrophobicity. Earlier work showed that 3-CH2-CO-NH-5 internucleoside amide linkages (abbreviated here as AM1) were well tolerated in the DNA strand of an A-type DNA-RNA heteroduplex.[4] Subsequently, we found that AM1 modifications did not change the thermal stability of RNA-RNA duplexes.[3] Most importantly, Iwase and-co-workers [5] recently showed that AM1 amides were well tolerated in the 3-overhangs of siRNAs.Taken together these data suggest that amides may be good mimics of phosphate linkages in RNA, however, beyond simple melting temperature measurements, structural and thermodynamic properties of amide-modified RNA have not been established. Herein we present the first comprehensive structural and thermodynamic study that clearly shows that AM1 linkages do not disturb the A-type structure, thermal stability and hydration of RNA
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DOI：
10.1002/anie.199402261
发表时间：
1994-02-01
期刊：
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION IN ENGLISH
影响因子：
--
作者：
DEMESMAEKER, A;WALDNER, A;FREIER, SM
通讯作者：
FREIER, SM
影响因子：
14.9
作者：
Rozners, E;Moulder, J
通讯作者：
Moulder, J
影响因子：
2.9
作者：
Spink, CH;Chaires, JB
通讯作者：
Chaires, JB
影响因子：
2.9
作者：
Pallan, Pradeep S.;von Matt, Peter;Egli, Martin
通讯作者：
Egli, Martin
影响因子：
15
作者：
Kolarovic, Andrej;Schweizer, Emma;Rozners, Eriks
通讯作者：
Rozners, Eriks