No abstract

This tutorial review describes the fundamental principles and recent advances in developing small molecule-based therapeutics for disease-associated RNAs.

While myriad non-coding RNAs are known to be essential in cellular processes and misregulated in diseases, the development of RNA-targeted small molecule probes has met with limited success. To elucidate guiding principles for selective small molecule:RNA recognition, we analyzed cheminformatic and shape-based descriptors for 104 RNA-targeted ligands with demonstrated biological activity (RNA-targeted BIoactive ligaNd Database, R-BIND). We then compared R-BIND to both FDA-approved small molecule drugs and RNA ligands without reported bioactivity. Several striking trends emerged for bioactive RNA ligands, including: i) compliance to medicinal chemistry rules; ii) distinctive structural features; and iii) enrichment in “rod-like” over other shapes. This work provides unique insights that directly facilitate the selection and synthesis of RNA-targeted libraries with the goal of efficiently identifying selective small molecule ligands for therapeutically relevant RNAs.