biostudies-literatureUrsu ANational Institute of Neurological Disorders and StrokeU.S. Department of DefenseNational Cancer InstituteNINDS NIH HHSNCI NIH HHSNational Institute of General Medical SciencesNIGMS NIH HHS7252-7270https://www.ebi.ac.uk/biostudies/studies/S-EPMC7707016biostudies-literatureUnknown49(20)The design and discovery of small molecule medicines has largely been focused on a small number of druggable protein families. A new paradigm is emerging, however, in which small molecules exert a biological effect by interacting with RNA, both to study human disease biology and provide lead therapeutic modalities. Due to this potential for expanding target pipelines and treating a larger number of human diseases, robust platforms for the rational design and optimization of small molecules interacting with RNAs (SMIRNAs) are in high demand. This review highlights three major pillars in this area. First, the transcriptome-wide identification and validation of structured RNA elements, or motifs, within disease-causing RNAs directly from sequence is presented. Second, we provide an overview oChemical Society reviewsDesign of small molecules targeting RNA structure from sequence.PMC7707016F31 NS110269W81XWH-18-0718R01 GM097455R01 GM133810R35 NS116846R00 GM112877R01 CA249180Angelbello AJChilds-Disney JLMeyer SMDisney MDAndrews RJMoss WNUrsu AO'Leary CAfalseDesign of small molecules targeting RNA structure from sequence.The design and discovery of small molecule medicines has largely been focused on a small number of druggable protein families. A new paradigm is emerging, however, in which small molecules exert a biological effect by interacting with RNA, both to study human disease biology and provide lead therapeutic modalities. Due to this potential for expanding target pipelines and treating a larger number of human diseases, robust platforms for the rational design and optimization of small molecules interacting with RNAs (SMIRNAs) are in high demand. This review highlights three major pillars in this area. First, the transcriptome-wide identification and validation of structured RNA elements, or motifs, within disease-causing RNAs directly from sequence is presented. Second, we provide an overview o2020-01-01T00:00:00Z2020 Oct2025-04-21T14:48:23.077Z2025-04-21T14:48:23.077ZS-EPMC77070163293568910.1039/d0cs00455c