DESIGNING CHEMICAL TOOLS TO INHIBIT RNA-BINDING PROTEINS

RNA-binding proteins (RBPs) regulate the life cycle of target mRNAs by controlling splicing, polyadenylation, stability, localization and translation, and they also modulate function of non-coding RNAs. Because of their crucial roles in many diverse cellular processes, RBPs are key targets for therapeutic intervention in a variety of human diseases ranging from cancers to neurodegeneration.

We have recently developed a new and unique computational approach for designing inhibitors of a given RBP, starting from its structure in complex with RNA. Briefly, our approach distills the cognate RNA to the functional groups that contribute most of the binding energy to the interaction, and then uses the precise three-dimensional geometry of these groups as a template for structure-based pharmacophore screening. This strategy leads to small-molecule inhibitors built on chemical scaffolds completely unrelated to RNA, and yet these compounds mimic the spatial arrangement of functional groups recognized by the target RBP. Because this approach is built in a rational way upon structural and energetic features of the protein-RNA complex, we expect that it will provide a robust and extensible way of developing inhibitors for many different RBPs.

We have validated this approach by applying it to three separate RBPs, and in each case we have identified inhibitors of our target proteins. Nonetheless, there is room for further improvement in the compounds we identify using this method. We are currently working to extend this computational approach by building target-specific combinatorial chemical libraries, and screening for hits in these custom libraries. This enhancement should allow us to improve the initial hit compounds’ potency, selectivity, and diversity.

With this further enhancement in place, we expect that our approach will provide new chemical tools to explore the biology of individual RBPs at unprecedented detail, and may even provide potential starting points for developing new therapeutic agents.