Drug Targeting RNA

Sequence-based design of small molecules targeting RNA structures to manipulate and study disease biology

A major challenge in science is exploiting new targets for medicine development. RNA is known to be directly involved in causing many diseases and yet is believed to be recalcitrant to small molecule targeting. Our programmatic focus has been on developing technologies to decipher which cellular RNAs are “druggable” targets for small molecules and which small molecules can target them. The focus of this talk is on the development of small molecules that target RNA structures that cause repeat expansion disorders, ca. 40 diseases each with no cure. Multiple small molecule classes have been developed to facilitate the study of these RNAs and to provide a foundation for medicine discovery. For example, structure-binding ligands have been endowed with the ability to affect degradation of repeat expansions to study molecular recognition of small molecules to RNA from cells to mouse models of disease. This approach found that mutant alleles that drive disease can be specifically targeted by structure-binding compounds, but not sequence-targeting oligonucleotides, and eliminated while selectively affecting disease phenotypes. Small molecules can also facilitate natural decay of repeat expansions in various ways that are mechanistically distinct, and we will describe these compounds and the prospects for using RNA quality control to eliminate disease-causing RNAs selectively with small molecules. These studies and others suggest that RNAs can be a rich source of small molecule targets and their biology can be programmably manipulated in many ways including targeted degradation.