Targeting RNA G-quadruplexes with small ligands

我们正在努力设计与G-四链RNA相互作用的小分子。这些富含鸟嘌呤(G)的四联体已知存在于病毒RNA中(包括SARS-CoV-2)。四分体由富含G的RNA序列形成非规范的DNA/RNA结构，形成平面结构，通过Hoogsten-氢键网络连接，并与中心碱金属离子配位。这些结构已被证明(在DNA中)主要通过堆积作用使用基于萘二亚胺(NDI)的结构来协调和稳定。我们希望进一步发展这一点来稳定RNA G-四链结构，并了解侧链变异和手性对NDIS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体NDI配体对G-四链体多个区域的协调作用。这些络合物稳定RNAG-四链的能力可能通过它们潜在的抗病毒特性而具有潜在的治疗应用。RNAG-四链的稳定可以防止病毒复制，因此，感染可以被平息。这项研究与EPSRC及其赠款有关，因为它将使用各种有机合成技术以及补充分析技术，如圆二色谱和等温量热法。同样，这也符合他们的文化宣言：“……为英国的长期利益带来影响……”他们的产出通过执行一个有可能在英国和世界各地作为治疗剂的一部分得到更广泛使用的项目来关注价值。

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.