RNA's capable of: catalysis (ribozymes), chemical modification of rRNA (snoRNA), regulation of retrotransposon (piwiRNA), transcriptional, and translational activity have been described. These biochemical functions demolish the confines placed on RNA, as stated in the central dogma (DNA-RNA-protein) and highlight the value of RNA as a target for therapeutic intervention, and basic science research.

Despite the potential of RNA-targeting therapeutics, the development of a small molecule "toolbox" of sequence-selective RNA-binding small molecules remains an imposing challenge. Currently, the number of small molecules that bind RNA with moderate sequence-selectivity and affinity is extremely small. Most often, researchers employ two distinct methods to identify small molecule ligands for an RNA target. In the first approach, a small molecule library is screened against the target RNA, and molecules with the highest affinity are identified. While this approach allows researchers to screen a medium to large number of molecules (depending on the screening method used), the binding-selectivity, as well as the ability of identified small molecuses to bind the target RNA in vivo are not revealed as part of the screen, and may therefore have little value as therapeutics, and reagents in basic science research (summarized in Fig 1).

In the second approach, a solid phase bound small molecule is allowed to interact with a large pool of RNA's, and RNA's with the highest affinity for the small molecule are identified through rounds of selection and amplification (SELEX). While this method allows researchers to identify a small molecule that binds the target RNA in a sequence-selective manner (by virtue of the fact that the selection conditions contain a large number of RNA's) the biological function of the selected RNA, if any, is unknown and cannot be predetermined, significantly limiting the utility of this method to target therapeutically relevant RNA's. What is more, like small molecule screening, selection-based approaches are most often performed in vitro, and does not apply pressure to select for small molecule - RNA pairs that interact in vivo. This limitation can impact the use of small molecule - RNA aptamer pairs in vivo, limiting their full potential (summarized in Fig 1).



Researchers in The McNaughton Group develop methods for identifying RNA-binding small molecules that combine features present in high-throughput small molecule screening, and selection-based methods. As a result, methods developed in our group enable researchers to explore large small molecule and RNA libraries in conjunction. In addition, researchers in The McNaughton Group design methods that link a high-affinity and sequence-selective small molecule - RNA interaction, to a measurable change in the cellular function of the small molecule-bound RNA. Once developed, we seek to apply these methods to identify RNA-targeting therapeutics (Fig 2).