Strategies for targeting RNA with small molecule drugs

Historically, therapeutic treatment of disease has been restricted to targeting proteins. Of the approximately 20,000 translated human proteins, approximately 1600 are associated with diseases. Strikingly, less than 15% of disease-associated proteins are predicted or known to be 'druggable.' While the concept and narrative of protein druggability continue to evolve with the development of novel technological and pharmacological advances, most of the human proteome remains undrugged. Recent genomic studies indicate that less than 2% of the human genome encodes for proteins, and while as much as 75% of the genome is transcribed, RNA has largely been ignored as a druggable target for therapeutic interventions.

This review delineates the theory and techniques involved in the development of small molecule inhibitors of RNAs from brute force, high-throughput screening technologies to de novo molecular design using computational machine and deep learning. We will also highlight the potential pitfalls and limitations of targeting RNA with small molecules.

Although significant advances have recently been made in developing systems to identify small molecule inhibitors of RNAs, many challenges remain. Focusing on RNA structure and ligand binding sites may help bring drugging RNA in line with traditional protein drug targeting.