RNA plays critical roles in biological processes and its dysregulation can causes disease. Thus, RNA is an important target for the development of therapeutics of chemical probes of function. Despite this, few small molecules, outside of antibiotics that target the bacterial ribosome, are known to modulate RNA function in cells. In this presentation, we describe a series of synergistic developments that can rationally design small molecules targeting RNA from sequence. Briefly, a target(s) RNA's sequence is converted to a secondary structure, or a composite of the motifs in the target RNA, and the motifs are then mined against a growing database of RNA motif-small molecule interactions, which are identified and annotated via two-dimensional combinatorial screening (2DCS) and other methods. We will also describe how lead small molecules are optimized for binding RNA via modular display on polymeric peptidomimetic scaffolds. Compounds have affinities and selectivites for RNA that targets that exceed those of natural proteins and are bioactive in both cellular and animal models of currently untreatable diseases such as myotonic dystrophy and fragile x-associated tremor ataxia syndrome.

Using peptidomimetics to design potent, modularly assembled compounds targeting RNA

247th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.