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

人类端粒DNA由数百个5'-TTAGGG重复序列组成，这些重复序列以大约200个核碱基的单链悬垂结尾。在生理条件下，这个序列可以折叠成四链螺旋排列，称为g -四重DNA。这种结构由于其在端粒维持中的作用而引起了极大的关注，因此它有可能成为开发新的抗癌疗法的靶点。因此，在过去的十年中，大量的小分子被开发出来，目的是选择性地结合和稳定g -四重体DNA。虽然含有4个重复5'-TTAGGG序列的单个g -四联体的结构已被详细研究，但对较长端粒序列形成的高阶结构知之甚少。后一种结构虽然很难在体外研究，但可能在生理上更相关，因为端粒DNA的单链悬垂可能折叠成含有多达十个连续的g -四联体的低聚物，这些低聚物由TTA间隔物连接。在这个项目中，我们建议开发一种靶向指导的合成方法来合成DNA结合物，协同结合两个连续的G4结构。这种方法可能产生对端粒G4s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可药性提供潜在的新途径。

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.