Synthesis of DNA binders for tandem repeats of G-quadruplex DNA in telomeric DNA: a target-guided synthetic approach

端粒 DNA 中 G 四链体 DNA 串联重复的 DNA 结合剂的合成：一种靶标引导的合成方法

• 批准号: 1955210
• 金额: --
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1955210
• 关键词: Synthesis; DNA; binders; tandem; repeats

Human telomeric DNA is composed of hundreds of 5'-TTAGGG repeats which end in a single-stranded overhang of around 200 nucleobases. Under physiological conditions, this sequence can fold into a tetra-stranded helical arrangement known as G-quadruplex DNA. This structure has attracted significant attention due to its proposed role in telomere maintenance and consequently its potential as target for the development of new anticancer therapies. Therefore, a large number of small molecules have been developed over the past decade with the aim of selectively binding and stabilising G-quadruplex DNA. While the structures of single G-quadruplexes containing four repeats of the 5'-TTAGGG sequence have been studied in detail, less is known about the higher-order structures formed by longer telomeric sequences. The latter structures, while difficult to study in vitro, are likely to be physiologically more relevant since the single-stranded overhang of telomeric DNA can potentially fold into oligomers containing as many as ten consecutive G-quadruplexes linked by TTA spacers.In this project, we propose to develop a target-guided synthetic approach to synthesise DNA binders that synergistically bind to two consecutive G4 structures. This approach is likely to yield binders with very high affinity and selectivity for telomeric G4s. This in turn will provide potential new avenues to study the drugability of these sequences.

人类端粒 DNA 由数百个 5'-TTAGGG 重复组成，其末端为约 200 个核碱基的单链突出端。在生理条件下，该序列可以折叠成四链螺旋排列，称为 G-四链体 DNA。这种结构因其在端粒维持中的作用及其作为开发新抗癌疗法的靶点的潜力而引起了极大的关注。因此，在过去的十年里，人们开发了大量的小分子，目的是选择性地结合和稳定 G-四链体 DNA。虽然已经详细研究了含有 5'-TTAGGG 序列四个重复的单 G-四链体的结构，但对较长端粒序列形成的高级结构知之甚少。后者的结构虽然难以在体外研究，但在生理上可能更相关，因为端粒 DNA 的单链突出端可能会折叠成含有多达 10 个由 TTA 间隔基连接的连续 G 四链体的寡聚体。在这个项目中，我们建议开发一种目标引导的合成方法来合成 DNA 结合剂，该结合剂可协同结合两个连续的 G4 结构。这种方法可能会产生对端粒 G4 具有非常高亲和力和选择性的结合物。这反过来将为研究这些序列的成药性提供潜在的新途径。