Chemical Modulation of DNA Replication along G-Quadruplex Based on Topology-Dependent Ligand Binding
Chemical Modulation of DNA Replication along G-Quadruplex Based on Topology-Dependent Ligand Binding
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DOI：
10.1021/jacs.1c05468
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发表时间：
2021-09-23
影响因子：
15
通讯作者：
Sugimoto, Naoki
中科院分区：
文献类型：
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作者：
Takahashi, Shuntaro;Kotar, Anita;Sugimoto, Naoki
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。由于存在多种 G4 拓扑结构，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根据不同的拓扑结构在 G4 处阻止了模板 DNA 的复制。例如，萘二酰亚胺衍生物与 G4 的 G 四联体结合，配体与来自人端粒的杂合 G4 类型的环区域之间存在额外的相互作用，从而有效地抑制了 G4 的复制。因此，这些抑制作用不仅依赖于稳定性，而且根据 G4 结构与 G4 配体相互作用的方式具有拓扑选择性。我们最初的方法被称为拓扑依赖性复制定量研究 (QSTR)，旨在评估复制率和 G4 稳定性之间的相关性。 QSTR 能够根据拓扑依赖性结合对配体进行系统分类。它还证明了定量确定 G4 配体如何控制复制中间状态和 G4 解旋动力学的准确性。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物。
Ligands that bind to and stabilize guaninequadruplex (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.