The ongoing discovery of functional yet non-protein coding RNA (ncRNA) sequences has led to a revolution in molecular biology that inspires novel approaches to disease diagnosis and therapy. Representative RNAs include bacterial riboswitches that control translation, viral RNA structures critical to replication, disease-dependent microRNAs that control mRNA levels and long noncoding RNAs (lncRNAs) that regulate complex gene expression networks. Despite this therapeutic potential, RNA is widely considered an “undruggable” target. Antisense oligonucleotides and related strategies are hindered by <i>in vivo</i> delivery challenges, and no small molecule drugs targeting RNAs other than the ribosome are currently available. Furthermore, our recent survey of the literature revealed less than one hundred reported chemical probes that target non-ribosomal RNA in biological systems. This slow progress is due in part to the dynamic nature and limited chemical functionality of RNA as well as to a shortage of small molecule targeting strategies. In order to gain fundamental insights into small molecule:RNA recognition, we are pursuing the parallel discovery of RNA-biased small molecule chemical space and RNA topological space privileged for differentiation. To begin, we identified chemical properties of biologically active RNA ligands that are distinct from those of protein-targeted ligands. Elaboration of four RNA binding scaffolds into a library enriched with these properties has led to improved recognition of medicinally relevant RNA targets. At the same time, we used principal component analysis to identify RNA topologies that can be differentially recognized by small molecules. We are currently expanding these studies with the ultimate goal of applying these insights to the rapid development of ligands with high affinity and specificity for a wide range of RNA targets, particularly those critical to cancer progression.

RNA-biased small molecules and privileged RNA topologies for selective small molecule: RNA recognition

254th National Meeting (2017)

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