Chemical matter that binds RNA
The recent "RNA revolution" has spurred the growth of studies focused on targeting disease-relevant RNAs with various chemical probes, from sequence-based antisense oligonucleotides to structure-based small molecules. Among these, small molecules attracted considerable research interests due to their feasibility in cellular delivery and chemical tunability. Similar to proteins, RNA molecules can fold into complex structures, affording ligandable pockets and a structural basis for small-molecule targeting. The discovery of RNA-targeted entities was initiated from antibiotic studies where bacterial ribosomal RNAs were targeted by a series of natural ligands. Revealing more diverse roles of RNA in biological systems has greatly expanded the scope and content of RNA targets, from viral/bacterial RNA elements to eukaryotic long non-coding RNAs, with structures ranging from simple secondary structural motifs to intricate tertiary or quaternary conformations. Additionally, the approaches of discovering RNA-biased chemical probes have evolved, from simply transferring protein-centric methods to developing more RNA-specific toolkits. The increasing number of identified RNA ligands has enriched our understanding of the privileged chemical structures suitable for RNA targeting, affording valuable resources to investigate molecular recognitions and design novel structures against a given RNA structure. The knowledge accumulated on distinct chemical space occupied by RNA ligands also led to several curated RNA-centric libraries and scaffold-based synthetic collections, whose sizes and diversities are still growing and updated with new findings. In this chapter, we focus on RNA ligands and discuss what type of chemical entities should be pursued for RNA targeting. We will first review common chemical scaffolds and their structural features with varied RNA-binding properties, from naturally discovered ligands to synthetic small molecules. Representative works on the construction of focused libraries will be introduced to explain library curation methods and the improved hit rates this strategy can achieve, followed by the discussion of methods to explore novel chemical space, a case study highlighting classes of ligands presented in this chapter, and future directions for the field of small-molecule RNA targeting.
