CRUK Biomolecular Structure Group, The School of Pharmacy, University of London, London, UK WC1N 1AX.
Chem Soc Rev. 2011 Dec;40(12):5867-92. doi: 10.1039/c1cs15067g. Epub 2011 Jul 25.
The intriguing structural diversity in folded topologies available to guanine-rich nucleic acid repeat sequences have made four-stranded G-quadruplex structures the focus of both basic and applied research, from cancer biology and novel therapeutics through to nanoelectronics. Distributed widely in the human genome as targets for regulating gene expression and chromosomal maintenance, they offer unique avenues for future cancer drug development. In particular, the recent advances in chemical and structural biology have enabled the construction of bespoke selective DNA based aptamers to be used as novel therapeutic agents and access to detailed structural models for structure based drug discovery. In this critical review, we will explore the important underlying characteristics of G-quadruplexes that make them functional, stable, and predictable nanoscaffolds. We will review the current structural database of folding topologies, molecular interfaces and novel interaction surfaces, with a consideration to their future exploitation in drug discovery, molecular biology, supermolecular assembly and aptamer design. In recent years the number of potential applications for G-quadruplex motifs has rapidly grown, so in this review we aim to explore the many future challenges and highlight where possible successes may lie. We will highlight the similarities and differences between DNA and RNA folded G-quadruplexes in terms of stability, distribution, and exploitability as small molecule targets. Finally, we will provide a detailed review of basic G-quadruplex geometry, experimental tools used, and a critical evaluation of the application of high-resolution structural biology and its ability to provide meaningful and valid models for future applications (255 references).
富含鸟嘌呤的核酸重复序列具有令人着迷的折叠拓扑结构多样性，这使得四链体 G-四链结构成为基础研究和应用研究的焦点，从癌症生物学和新型疗法到纳米电子学。它们广泛分布在人类基因组中，作为调节基因表达和染色体维持的靶点，为未来的癌症药物开发提供了独特的途径。特别是，化学和结构生物学的最新进展使得构建了专门针对 DNA 的选择性适配体，可用作新型治疗剂，并获得了基于结构的药物发现的详细结构模型。在这篇重要的综述中，我们将探讨 G-四链体的重要基本特征，这些特征使它们成为功能性、稳定和可预测的纳米支架。我们将回顾折叠拓扑结构、分子界面和新的相互作用表面的当前结构数据库，并考虑在药物发现、分子生物学、超分子组装和适配体设计中对其进行未来开发。近年来，G-四链体基序的潜在应用数量迅速增长，因此在本综述中，我们旨在探讨许多未来的挑战，并尽可能地突出可能的成功之处。我们将比较 DNA 和 RNA 折叠 G-四链体在稳定性、分布和作为小分子靶标可开发性方面的异同。最后，我们将详细回顾基本的 G-四链体几何形状、实验工具的应用，并对高分辨率结构生物学的应用及其为未来应用提供有意义和有效的模型的能力进行批判性评估（255 篇参考文献）。
