Ligands that bind to and stabilize guanine-quadruplex (G4) structures to regulate DNA replication have therapeutic potential for cancer and neurodegenerative diseases. Because there are several G4 topologies, ligands that bind to their specific types may have the ability to preferentially regulate the replication of only certain genes. Here, we demonstrated that binding ligands stalled the replication of template DNA at G4, depending on different topologies. For example, naphthalene diimide derivatives bound to the G-quartet of G4 with an additional interaction between the ligand and the loop region of a hybrid G4 type from human telomeres, which efficiently repressed the replication of the G4. Thus, these inhibitory effects were not only stability-dependent but also topology-selective based on the manner in which G4 structures interacted with G4 ligands. Our original method, referred to as a quantitative study of topology-dependent replication (QSTR), was developed to evaluate correlations between replication rate and G4 stability. QSTR enabled the systematic categorization of ligands based on topology-dependent binding. It also demonstrated accuracy in determining quantitatively how G4 ligands control the intermediate state of replication and the kinetics of G4 unwinding. Hence, the QSTR index would facilitate the design of new drugs capable of controlling the topology-dependent regulation of gene expression.

中文翻译：

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基于拓扑依赖性配体结合的 G-四链体 DNA 复制的化学调控

结合并稳定鸟嘌呤四链体 (G4) 结构以调节 DNA 复制的配体具有治疗癌症和神经退行性疾病的潜力。因为有几种 G4 拓扑，与其特定类型结合的配体可能具有优先调节某些基因复制的能力。在这里，我们证明了结合配体在 G4 时停止了模板 DNA 的复制，这取决于不同的拓扑结构。例如，萘二亚胺衍生物与 G4 的 G-四联体结合，配体与来自人类端粒的杂合 G4 类型的环区域之间存在额外的相互作用，这有效地抑制了 G4 的复制。因此，基于 G4 结构与 G4 配体相互作用的方式，这些抑制作用不仅依赖于稳定性，而且还具有拓扑选择性。我们最初的方法，称为拓扑依赖复制 (QSTR) 的定量研究，旨在评估复制率和 G4 稳定性之间的相关性。QSTR 能够基于拓扑依赖性结合对配体进行系统分类。它还证明了在定量确定 G4 配体如何控制复制的中间状态和 G4 展开的动力学方面的准确性。因此，QSTR 指数将有助于设计能够控制基因表达的拓扑依赖性调节的新药。开发用于评估复制率和 G4 稳定性之间的相关性。QSTR 能够基于拓扑依赖性结合对配体进行系统分类。它还证明了在定量确定 G4 配体如何控制复制的中间状态和 G4 展开的动力学方面的准确性。因此，QSTR 指数将有助于设计能够控制基因表达的拓扑依赖性调节的新药。开发用于评估复制率和 G4 稳定性之间的相关性。QSTR 能够基于拓扑依赖性结合对配体进行系统分类。它还证明了在定量确定 G4 配体如何控制复制的中间状态和 G4 展开的动力学方面的准确性。因此，QSTR 指数将有助于设计能够控制基因表达的拓扑依赖性调节的新药。