High‐Resolution DNA Structures and Drug Targeting of Short Tandem Repeats in Repeat Expansion Disorders

Short tandem repeats (STRs) are DNA sequences with repeating units of 1–6 nucleotides widely distributed in the human genome. Expansions of STRs cause over 50 repeat expansion disorders, owing to their ability to adopt noncanonical DNA structures that drive genetic instabilities. Targeting the three‐dimensional (3D) structures of STRs has emerged as a promising strategy for disease therapy. In this review, we organize their predominant non‐B DNA folds including slipped‐strand hairpins and mismatch‐containing duplexes by CNG repeats, mini‐dumbbell folds by pyrimidine‐rich repeats, G‐quadruplexes by guanine‐rich repeats, and triplex/zipper‐hairpin conformations by other repeats. We delineate how sequence‐encoded mismatch geometries, loop architectures, and groove dimensions create molecular recognition surfaces. We further survey small‐molecule ligands that recognize the non‐B DNA structures of STRs, assess the pharmacological limitations of non‐B DNA structure‐targeting ligands, and discuss challenges in structure‐guided drug discovery arising from structural polymorphisms and conformational dynamics of STRs. We also highlight how molecular dynamics simulations bridge the resolution gap between static structural snapshots and dynamic conformational ensembles, and outline how multimodal structural biology of STRs will advance structure‐guided ligand discovery.