Targeting RNA G-quadruplexes with small ligands

用小配体靶向 RNA G 四链体

• 批准号: 2601841
• 金额: --
• 依托单位: University of Bath
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2601841
• 关键词: Targeting; RNA; quadruplexes; small; ligands

We are working to design small molecules that interact with G-quadruplex RNA. These guanine (G) rich tetrads are known to exist in viral RNA (including in SARS-Cov-2). The tetrads form as non canonical DNA/RNA structures from G-rich sequences of RNA to give a planar structure connected via Hoogsten-hydrogen bonding network and coordinated to a central alkali metal ion. These structures have been shown (in DNA) to be coordinated and stabilised using naphthalene diimide (NDI) based structures primarily via stacking interactions. We hope to develop this further to stabilise RNA G-quadruplex structures, and understand the effects of side-chain variance and chirality on the ability of the NDIs to promote changes in stability. Furthermore, we aim to explore the effect of a dimerised NDI ligand to coordinate multiple areas of the G-quadruplex. The ability of these complexes to stabilise RNA G-quadruplexes could have potential therapeutic applications via their potential anti-viral properties. Stabilisation of RNA G-quadruplexes could prevent a virus from replicating and therefore, an infection can be quashed. This research is relevant to EPSRC and their grant as it will use a variety of organic synthetic techniques along with use of complementary analytical techniques, such as circular dichroism and isothermal calorimetry. Equally, it matches their culture statement of "...delivering impact for the long-term benefit of the UK..." and their output focused values by performing a project that has potential for wider use in the UK and around the world as part of a therapeutic agent.

我们正在努力设计与 G-四链体 RNA 相互作用的小分子。已知这些富含鸟嘌呤 (G) 的四分体存在于病毒 RNA（包括 SARS-Cov-2）中。四分体是由富含 G 的 RNA 序列形成的非规范 DNA/RNA 结构，形成通过 Hoogsten 氢键网络连接并与中心碱金属离子配位的平面结构。这些结构已被证明（在 DNA 中）主要通过堆积相互作用使用基于萘二酰亚胺 (NDI) 的结构进行协调和稳定。我们希望进一步发展这一点以稳定 RNA G 四链体结构，并了解侧链变异和手性对 NDI 促进稳定性变化的能力的影响。此外，我们的目标是探索二聚化 NDI 配体协调 G-四链体多个区域的效果。这些复合物稳定 RNA G 四链体的能力可能通过其潜在的抗病毒特性而具有潜在的治疗应用。 RNA G 四链体的稳定可以防止病毒复制，因此可以消除感染。这项研究与 EPSRC 及其资助相关，因为它将使用各种有机合成技术以及补充分析技术，例如圆二色性和等温量热法。同样，它通过执行一个有潜力作为治疗剂的一部分在英国和世界各地广泛使用的项目，符合他们的文化宣言“......为英国的长期利益提供影响......”以及他们以产出为中心的价值观。