Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, Tennessee 37232-0146, USA.
Chem Biodivers. 2010 Jan;7(1):60-89. doi: 10.1002/cbdv.200900177.
Chemically modified nucleic acids (CNAs) are widely explored as antisense oligonucleotide or small interfering RNA (siRNA) candidates for therapeutic applications. CNAs are also of interest in diagnostics, high-throughput genomics and target validation, nanotechnology and as model systems in investigations directed at a better understanding of the etiology of nucleic acid structure, as well as the physicochemical and pairing properties of DNA and RNA, and for probing protein-nucleic acid interactions. In this article, we review research conducted in our laboratory over the past two decades with a focus on crystal-structure analyses of CNAs and artificial pairing systems. We highlight key insights into issues ranging from conformational distortions as a consequence of modification to the modulation of pairing strength, and RNA affinity by stereoelectronic effects and hydration. Although crystal structures have only been determined for a subset of the large number of modifications that were synthesized and analyzed in the oligonucleotide context to date, they have yielded guiding principles for the design of new analogs with tailor-made properties, including pairing specificity, nuclease resistance, and cellular uptake. And, perhaps less obviously, crystallographic studies of CNAs and synthetic pairing systems have shed light on fundamental aspects of DNA and RNA structure and function that would not have been disclosed by investigations solely focused on the natural nucleic acids.
化学修饰的核酸（CNAs）被广泛探索作为反义寡核苷酸或小干扰 RNA（siRNA）候选物用于治疗应用。CNA 在诊断、高通量基因组学和靶标验证、纳米技术以及作为模型系统方面也具有重要意义，可用于深入了解核酸结构的病因学、以及 DNA 和 RNA 的理化和配对特性，并用于探测蛋白质-核酸相互作用。在本文中，我们回顾了我们实验室在过去二十年中进行的研究，重点是对 CNA 和人工配对系统的晶体结构分析。我们强调了从修饰引起的构象扭曲到立体电子效应和水合作用对配对强度和 RNA 亲和力的调节等问题的关键见解。尽管迄今为止仅为在寡核苷酸背景下合成和分析的大量修饰中的一小部分确定了晶体结构，但它们为设计具有定制特性的新类似物提供了指导原则，包括配对特异性、核酸酶抗性和细胞摄取。而且，也许不太明显的是，对 CNA 和合成配对系统的晶体学研究揭示了 DNA 和 RNA 结构和功能的基本方面，如果仅专注于天然核酸进行研究，这些方面是不会被揭示的。
