Small molecule-RNA targeting: starting with the fundamentals.

The structural and regulatory elements in therapeutically relevant RNAs offer many opportunities for targeting by small molecules, yet fundamental understanding of what drives selectivity in small molecule:RNA recognition has been a recurrent challenge. In particular, RNAs tend to be more dynamic and offer less chemical functionality than proteins, and biologically active ligands must compete with the highly abundant and highly structured RNA of the ribosome. Indeed, the only small molecule drug targeting RNA other than the ribosome was just approved in August 2020, and our recent survey of the literature revealed fewer than 150 reported chemical probes that target non-ribosomal RNA in biological systems. This Feature outlines our efforts to improve small molecule targeting strategies and gain fundamental insights into small molecule:RNA recognition by analyzing patterns in both RNA-biased small molecule chemical space and RNA topological space privileged for differentiation. First, we synthesized libraries based on RNA binding scaffolds that allowed us to reveal general principles in small molecule:recognition and to ask precise chemical questions about drivers of affinity and selectivity. Elaboration of these scaffolds has led to recognition of medicinally relevant RNA targets, including viral and long noncoding RNA structures. More globally, we identified physicochemical, structural, and spatial properties of biologically active RNA ligands that are distinct from those of protein-targeted ligands, and we have provided the dataset and associated analytical tools as part of a publicly available online platform to facilitate RNA ligand discovery. At the same time, we used pattern recognition protocols to identify RNA topologies that can be differentially recognized by small molecules and have elaborated this technique to visualize conformational changes in RNA secondary structure. These fundamental insights into the drivers of RNA recognition in vitro have led to functional targeting of RNA structures in biological systems. We hope that these initial guiding principles, as well as the approaches and assays developed in their pursuit, will enable rapid progress toward the development of RNA-targeted chemical probes and ultimately new therapeutic approaches to a wide range of deadly human diseases.