Unveiling RNA ligands: Harnessing NMR for hit generation

In recent decades, there has been extraordinary progress in the discovery of biomacromolecules essential for the occurrence and progression of diseases, providing new and more effective perspectives for drug discovery. The discovery and development of new drugs are vital to healthcare, as most existing drugs target protein-based biomolecules such as enzymes and receptors. Nevertheless, only a small part of the genome encodes for proteins, while a large portion is transcribed into RNA. Moving beyond proteins, RNA is emerging as a promising target, offering a vast, largely unexplored chemical space for therapy. The knowledge gained from applying Nuclear Magnetic Resonance (NMR) spectroscopy to protein-target-based drug discovery can play a key role in advancing the discovery of RNA-targeting drugs. NMR can significantly contribute not only to determining RNA structures but also to uncovering new small molecules with potential as drugs through innovative mechanisms of action. This review aims to explore an emerging field of research that uses RNA as a therapeutic target, focusing on how NMR can contribute to the discovery of hit-to-lead compounds and provide information on ligand-RNA interactions to drive the optimisation and eventual clinical application of these compounds.