RNA–Small-Molecule Interaction: Challenging the “Undruggable” Tag

RNA targeting, specifically with small molecules, is a relatively new and rapidly emerging avenue with the promise to expand the target space in the drug discovery field. From being "disregarded" as an "undruggable" messenger molecule to FDA approval of an RNA-targeting small-molecule drug Risdiplam, a radical change in perspective toward RNA has been observed in the past decade. RNAs serve important regulatory functions beyond canonical protein synthesis, and their dysregulation has been reported in many diseases. A deeper understanding of RNA biology reveals that RNA molecules can adopt a variety of structures, carrying defined binding pockets that can accommodate small-molecule drugs. Due to its functional diversity and structural complexity, RNA can be perceived as a prospective target for therapeutic intervention. This perspective highlights the proof of concept of RNA–small-molecule interactions, exemplified by targeting of various transcripts with functional modulators. The advent of RNA-oriented knowledge would help expedite drug discovery.