Abstract: RNA is emerging as a chemically tractable therapeutic target rather than merely an intermediary between DNA and proteins. Its diverse secondary, tertiary, and quaternary structures create ligandable environments for small molecules, although dynamic conformations, electrostatic surfaces, and recurrent motifs complicate selective targeting. Cryptic RNA pockets are particularly promising sites that are weakly populated or inaccessible in the unbound state but become exposed or reorganized upon ligand binding. Riboswitches provide natural models for this mechanism, while recent studies have extended RNA targeting to hairpins, internal loops, bulges, G-quadruplexes, viral regulatory elements, precursor microRNAs, long non-coding RNAs, and RNA–protein interfaces. Advances in dynamic-ensemble screening, fragment-based discovery, RNA-focused libraries, sequence-based design, chemical probing, and computational pocket prediction are expanding the druggable RNA landscape. The Cbl riboswitch illustrates how ligand-induced nucleotide displacement can reveal a cryptic pocket for synthetic ligand recognition. RIBOTACs and targeted-cleavage conjugates further connect RNA binding with cellular function, while risdiplam demonstrates clinical feasibility of small-molecule RNA modulation. This mini-review discusses structural principles, discovery strategies, representative applications, challenges, and emerging technologies for developing sequence-selective RNA therapeutics through integrated structure-guided medicinal chemistry.
Keywords: RNA targeting, small molecules, cryptic pockets, riboswitch, RIBOTAC, Inforna