Structure-function-guided drug development efforts to target lncRNAs.

Abstract

Long noncoding RNAs (lncRNAs) play a pivotal role in regulating cellular processes, and their dysregulation has been linked to the progression of disease. Understanding the structural characteristics, protein interactions, and expression dynamics of lncRNAs is essential for deciphering their functional mechanisms. Recent advancements in structural probing techniques have unveiled critical structural motifs and RNA-protein interfaces that contribute to lncRNA dysfunction. Furthermore, developing small molecules, antisense oligonucleotides, and peptidomimetic-based therapeutic agents that target these motifs and interfaces presents promising strategies for treating lncRNA-mediated diseases. This review provides fresh insights into how lncRNAs contribute to disease pathogenesis, focusing on well-characterized lncRNAs, including MALAT1, HOTAIR, GAS5, NEAT1, and XIST as case studies, and explores potential therapeutic agents targeting these lncRNAs to support future drug development efforts.