Solving the Sequence-Selective RNA Binding Problem

Project Collaborator:

• Dr. Charles Thornton

Disulfide dimers of these four compounds selectively bind (CUG) repeat RNA.

Through the efforts of a number of laboratories, we now have a code that allows us to synthesize high-affinity, high-selectivity ligands for DNA if we know the sequence. Developing an analogous code for RNA constitutes a landmark challenge in science.

Using Resin-Bound Dynamic Combinatorial Chemistry (RBDCC) to expand on a general design hypothesis for RNA-binding compounds, we identified the first synthetic compounds able to bind (CUG) repeat RNAs, a toxic RNA important in type 1 myotonic dystrophy. RBDCC also allowed us to discover compounds binding an RNA target that regulates frameshifting in HIV. Current efforts are focused on enhancing the affinity and selectivity of our lead compounds via a combination of medicinal chemistry and biophysical experiments, and in the identification of other novel RNA-binding compounds via directed design and RBDCC.

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