Targeting RNA G-quadruplexes with small ligands

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中（包括SARS-Cov-2）。四分体由RNA的富G序列形成非典型的DNA/RNA结构，通过Hoogsten-氢键网络连接并与中心碱金属离子配位，得到平面结构。这些结构已被证明（在DNA中）是协调和稳定的使用萘二酰亚胺（NDI）为基础的结构，主要是通过堆叠相互作用。我们希望进一步发展这一点来稳定RNA G-四链体结构，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NDI配体协调G-四链体的多个区域的效果。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及其资助有关，因为它将使用各种有机合成技术，沿着使用互补的分析技术，如圆二色性和等温量热法。同样，它符合他们的文化声明“......为英国的长远利益带来影响“和他们的输出集中的价值，通过执行一个项目，有可能在英国和世界各地更广泛地使用作为治疗剂的一部分。

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.