Targeting RNA G-quadruplexes with small ligands

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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.