Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS) and Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1XQ, United Kingdom.
Acc Chem Res. 2020 Oct 20;53(10):2286-2298. doi: 10.1021/acs.accounts.0c00415. Epub 2020 Sep 30.
DNA is the molecule responsible for the storage and transmission of the genetic information in living organisms. The expression of this information is highly regulated. In eukaryotes, it is achieved mainly at the transcription level thanks to specialized proteins called (TFs) that recognize specific DNA sequences, thereby promoting or inhibiting the transcription of particular genes. In many cases, TFs are present in the cell in an inactive form but become active in response to an external signal, which might modify their localization and DNA binding properties or modulate their interactions with the rest of the transcriptional machinery. As a result of the crucial role of TFs, the design of synthetic peptides or miniproteins that can emulate their DNA binding properties and eventually respond to external stimuli is of obvious interest. On the other hand, although the B-form double helix is the most common DNA secondary structure, it is not the only one with an essential biological function. Guanine quadruplexes (GQs) have received considerable attention due to their critical role in the regulation of gene expression, which is usually associated with a change in the GQ conformation. Thus, the development of GQ probes whose properties can be controlled using external signals is also of significant relevance.In this Account, we present a summary of the recent efforts toward the development of stimuli-responsive synthetic DNA binders with a particular emphasis on our own contributions. We first introduce the structure of B and GQ DNAs, and some of the main factors underlying their selective recognition. We then discuss some of the different approaches used for the design of stimulus-mediated DNA binders. We have organized our discussion according to whether the interaction takes place with duplex or guanine quadruplex DNAs, and each section is divided according to the nature of the stimulus (i.e., physical or chemical). Regarding physical stimuli, light (through the incorporation of photolabile protecting groups or photoisomerizable agents) is the most common input for the activation/deactivation of DNA binding events. With respect to chemical signals, the use of metals (through the incorporation of metal-coordinating groups in the DNA binding agent) has allowed the development of a wide range of stimuli-responsive DNA binders. More recently, redox-based systems have also been used to control DNA interactions.This Account ends with a "Conclusions and Outlook" section highlighting some of the general lessons that have been learned and future directions toward further advancing the field.
DNA 是负责存储和传递生物体内遗传信息的分子。该信息的表达受到高度调控。在真核生物中，主要通过称为转录因子 (TFs) 的专门蛋白质在转录水平上实现，这些蛋白质识别特定的 DNA 序列，从而促进或抑制特定基因的转录。在许多情况下，TFs 以无活性形式存在于细胞中，但会对外界信号做出反应而变得活跃，从而改变其定位和 DNA 结合特性，或调节与转录机器其余部分的相互作用。由于 TFs 具有至关重要的作用，因此设计能够模拟其 DNA 结合特性并最终对外界刺激做出响应的合成肽或小蛋白具有明显的意义。另一方面，尽管 B 型双螺旋是最常见的 DNA 二级结构，但它并不是唯一具有重要生物学功能的结构。由于其在基因表达调控中的关键作用，鸟嘌呤四链体 (GQ) 受到了相当多的关注，这种调控通常与 GQ 构象的变化有关。因此，开发可以使用外部信号控制其性质的 GQ 探针也具有重要意义。
在本综述中，我们总结了最近在开发具有刺激响应性的合成 DNA 结合剂方面的努力，特别强调了我们自己的贡献。我们首先介绍了 B 型和 GQ DNA 的结构，以及它们选择性识别的一些主要因素。然后，我们讨论了用于设计刺激介导的 DNA 结合剂的一些不同方法。我们根据相互作用是发生在双链体还是鸟嘌呤四链体 DNA 上，以及根据刺激的性质（即物理或化学）对讨论进行了组织。关于物理刺激，光（通过引入光不稳定保护基团或光致变色试剂）是激活/失活 DNA 结合事件最常用的输入。关于化学信号，通过在 DNA 结合剂中引入金属配位基团，已经可以开发出广泛的刺激响应性 DNA 结合剂。最近，氧化还原系统也被用于控制 DNA 相互作用。
本综述以“结论和展望”部分结束，该部分突出了一些已经学到的一般经验教训和进一步推进该领域的未来方向。
