RNA adopts 3D structures that confer varied functional roles in human biology and dysfunction in disease. Approaches to therapeutically target RNA structures with small molecules are being actively pursued, aided by key advances in the field including the development of computational tools that predict evolutionarily conserved RNA structures, as well as strategies that expand mode of action and facilitate interactions with cellular machinery. Existing RNA-targeted small molecules use a range of mechanisms including directing splicing — by acting as molecular glues with cellular proteins (such as branaplam and the FDA-approved risdiplam), inhibition of translation of undruggable proteins and deactivation of functional structures in noncoding RNAs. Here, we describe strategies to identify, validate and optimize small molecules that target the functional transcriptome, laying out a roadmap to advance these agents into the next decade.

RNA 采用 3D 结构，赋予人类生物学和疾病功能障碍不同的功能作用。人们正在积极寻求用小分子治疗性靶向 RNA 结构的方法，这得益于该领域的关键进展，包括预测进化保守 RNA 结构的计算工具的开发，以及扩展作用模式和促进与细胞机器相互作用的策略。现有的 RNA 靶向小分子使用一系列机制，包括指导剪接——作为细胞蛋白质的分子粘合剂（例如 branaplam 和 FDA 批准的 risdiplam）、抑制不可成药蛋白质的翻译以及使非编码 RNA 中的功能结构失活。在这里，我们描述了识别、验证和优化针对功能转录组的小分子的策略，并制定了将这些药物推进到下一个十年的路线图。