Probing Bioactive Chemical Space to Discover RNA-Targeted Small Molecules

Abstract

The use of small molecules to modulate RNA structure and function has become invaluable for studying the many roles of RNA in biological processes1 as well as discovering effective therapeutic treatments.2-5 Early on, the promise of RNA as a ‘druggable’ target was demonstrated by the identification of several RNA-targeting small molecule classes such as aminoglycosides.6, 7 These ligands bound highly abundant and structured ribosomal RNA (rRNA) and inhibited protein synthesis in prokaryotes, leading to the development of numerous FDA-approved antibiotics.8 Over the last 25 years, momentous efforts to target non-ribosomal RNAs, which are less studied and have lower abundance (< 10% of total RNA), have yielded a modest collection of ~150 biologically active small molecules that target bacterial, fungal, viral, and mammalian RNAs.9, 10 Notable examples include Phase 2 clinical trial candidate Branaplam11 and recently FDA-approved Risdiplam12, both of which were developed to target mRNA splicing and treat spinal muscular atrophy. While immensely promising, the field of targeting RNA with small molecules is still in its infancy; we have only begun to elucidate and evaluate the guiding principles that govern RNA:small molecule recognition.