Unexpected origins of the enhanced pairing affinity of 2'-fluoro-modified RNA.
Unexpected origins of the enhanced pairing affinity of 2'-fluoro-modified RNA.
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DOI：
10.1093/nar/gkq1270
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发表时间：
2011-04
影响因子：
14.9
通讯作者：
Egli M
中科院分区：
文献类型：
--
作者：
Pallan PS;Greene EM;Jicman PA;Pandey RK;Manoharan M;Rozners E;Egli M
目前正在对各种化学修饰进行评估，以提高作为体内基因沉默反义剂的短干扰RNA(SiRNA)双链的有效性。在迄今评估的2‘-核糖修饰中，2’-脱氧-2‘-氟-RNA(2’-F-RNA)具有RNA干扰(RNAi)应用的独特性质。因此，2‘-F修饰的核苷酸在导向(反义)和客体(正义)siRNA链中具有很好的耐受性，相应的双链与未修饰的siRNA相比缺乏免疫刺激作用，增强了核酸酶的抗性，并显示出更好的效果。为了确定RNA和2‘-F-RNA不同行为的潜在来源，我们对完全和部分2’-F-修饰的RNA进行了热力学和X射线结晶学分析。令人惊讶的是，我们发现2‘-F-RNA相对于RNA的配对亲和力增加，并不像通常认为的那样，是有利的熵贡献(构象前组织)的结果，而主要是基于焓的。高分辨和渗透胁迫下的晶体结构表明，2‘-F-RNA双链的水合程度低于RNA双链。前者的焓驱动、更高的稳定性暗示了这样一种可能性，即2‘-取代基除了在构象雕刻中发挥重要作用外，在调节沃森-克里克碱基配对强度和潜在的π-π堆积相互作用方面也被低估了。
Various chemical modifications are currently being evaluated for improving the efficacy of short interfering RNA (siRNA) duplexes as antisense agents for gene silencing in vivo. Among the 2′-ribose modifications assessed to date, 2′deoxy-2′-fluoro-RNA (2′-F-RNA) has unique properties for RNA interference (RNAi) applications. Thus, 2′-F-modified nucleotides are well tolerated in the guide (antisense) and passenger (sense) siRNA strands and the corresponding duplexes lack immunostimulatory effects, enhance nuclease resistance and display improved efficacy in vitro and in vivo compared with unmodified siRNAs. To identify potential origins of the distinct behaviors of RNA and 2′-F-RNA we carried out thermodynamic and X-ray crystallographic analyses of fully and partially 2′-F-modified RNAs. Surprisingly, we found that the increased pairing affinity of 2′-F-RNA relative to RNA is not, as commonly assumed, the result of a favorable entropic contribution (‘conformational preorganization’), but instead primarily based on enthalpy. Crystal structures at high resolution and osmotic stress demonstrate that the 2′-F-RNA duplex is less hydrated than the RNA duplex. The enthalpy-driven, higher stability of the former hints at the possibility that the 2′-substituent, in addition to its important function in sculpting RNA conformation, plays an underappreciated role in modulating Watson–Crick base pairing strength and potentially π–π stacking interactions.
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影响因子：
4.3
作者：
Dunitz, Jack. D.;Schweizer, W. Bernd
通讯作者：
Schweizer, W. Bernd
影响因子：
15
作者：
Guckian, KM;Schweitzer, BA;Kool, ET
通讯作者：
Kool, ET
影响因子：
2.9
作者：
Braasch, DA;Jensen, S;Corey, DR
通讯作者：
Corey, DR
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL
影响因子：
--
作者：
BONDI, A
通讯作者：
BONDI, A