Department of Chemistry, Clemson University, USA.
Acc Chem Res. 2011 Feb 15;44(2):134-46. doi: 10.1021/ar100113q. Epub 2010 Nov 12.
A DNA duplex can be recognized sequence-specifically in the major groove by an oligodeoxynucleotide (ODN). The resulting structure is a DNA triple helix, or triplex. The scientific community has invested significant research capital in the study of DNA triplexes because of their robust potential for providing new applications, including molecular biology tools and therapeutic agents. The triplex structures have inherent instabilities, however, and the recognition of DNA triplexes by small molecules has been attempted as a means of strengthening the three-stranded complex. Over the decades, the majority of work in the field has focused on heterocycles that intercalate between the triplex bases. In this Account, we present an alternate approach to recognition and stabilization of DNA triplexes. We show that groove recognition of nucleic acid triple helices can be achieved with aminosugars. Among these aminosugars, neomycin is the most effective aminoglycoside (groove binder) for stabilizing a DNA triple helix. It stabilizes both the TAT triplex and mixed-base DNA triplexes better than known DNA minor groove binders (which usually destabilize the triplex) and polyamines. Neomycin selectively stabilizes the triplex (TAT and mixed base) without any effect on the DNA duplex. The selectivity of neomycin likely originates from its potential and shape complementarity to the triplex Watson-Hoogsteen groove, making it the first molecule that selectively recognizes a triplex groove over a duplex groove. The groove recognition of aminoglycosides is not limited to DNA triplexes, but also extends to RNA and hybrid triple helical structures. Intercalator-neomycin conjugates are shown to simultaneously probe the base stacking and groove surface in the DNA triplex. Calorimetric and spectrosocopic studies allow the quantification of the effect of surface area of the intercalating moiety on binding to the triplex. These studies outline a novel approach to the recognition of DNA triplexes that incorporates the use of noncompeting binding sites. These principles of dual recognition should be applicable to the design of ligands that can bind any given nucleic acid target with nanomolar affinities and with high selectivity.
DNA 双链可以通过寡脱氧核苷酸（ODN）特异性识别主沟，从而形成 DNA 三螺旋或三联体。科学界在 DNA 三螺旋的研究上投入了大量的研究资金，因为它们具有提供新应用的强大潜力，包括分子生物学工具和治疗剂。然而，三螺旋结构具有固有的不稳定性，因此尝试了小分子识别 DNA 三螺旋，作为增强三链复合物的一种手段。几十年来，该领域的大部分工作都集中在插入三螺旋碱基之间的杂环上。在本综述中，我们提出了一种识别和稳定 DNA 三螺旋的替代方法。我们表明，通过氨基糖可以实现核酸三螺旋的沟识别。在这些氨基糖中，新霉素是稳定 DNA 三螺旋最有效的氨基糖苷（沟结合物）。它比已知的 DNA 小沟结合物（通常使三螺旋不稳定）和聚胺更有效地稳定 TAT 三螺旋和混合碱基 DNA 三螺旋。新霉素选择性地稳定三螺旋（TAT 和混合碱基），而对 DNA 双链没有任何影响。新霉素的选择性可能源于其与三螺旋 Watson-Hoogsteen 沟的潜在和形状互补性，使其成为第一个选择性识别三螺旋沟而不是双链沟的分子。氨基糖苷的沟识别不仅限于 DNA 三螺旋，还扩展到 RNA 和杂交三螺旋结构。已证明插入剂-新霉素缀合物可同时探测 DNA 三螺旋中的碱基堆积和沟表面。量热法和光谱法研究允许定量测量插入部分的表面积对三螺旋结合的影响。这些研究概述了一种识别 DNA 三螺旋的新方法，该方法结合了使用非竞争结合位点。这些双重识别的原则应该适用于设计可以与纳米摩尔亲和力和高选择性结合任何给定核酸靶标的配体。
