“Drugging RNA with Small Molecules – A Structure-based Approach”
Jennifer Petter | Arrakis
RNA structures play a key role in the complex regulatory network that governs RNA function, particularly splicing and translation. These structures are therapeutically compelling targets for the interdiction of RNA function. Most current therapeutic agents that bind directly to RNA are either antibiotics blocking bacterial ribosome function or oligonucleotides with their attendant pharmaceutical limitations. We are pursuing small molecules that penetrate membranes and bind to specific mRNAs and pre-mRNAs. This requires that we identify ligandable, functionally essential RNA sub-structures and druglike small molecules that bind to those structures selectively and thereby modulate their function. This presentation will focus on some of the unique challenges of drugging RNA and offer some solutions to those challenges. Specifically, we will discuss a promising structure in a MYC transcript, the binding mode of small-molecule ligands, the demonstration of target engagement in cells, the mechanisms that yield selectivity, the impact of this binding event on translation, and evidence that the translational outcome can be attributed to RNA binding.
