Duke University School of Medicine, Department of Biochemistry, Durham, North Carolina, USA.
Princeton University, Department of Chemical and Biological Engineering, Princeton, New Jersey, USA.
Chem Soc Rev. 2021 Mar 1;50(4):2224-2243. doi: 10.1039/d0cs01261k.
Recent advances in our understanding of RNA biology have uncovered crucial roles for RNA in multiple disease states, ranging from viral and bacterial infections to cancer and neurological disorders. As a result, multiple laboratories have become interested in developing drug-like small molecules to target RNA. However, this development comes with multiple unique challenges. For example, RNA is inherently dynamic and has limited chemical diversity. In addition, promiscuous RNA-binding ligands are often identified during screening campaigns. This Tutorial Review overviews important considerations and advancements for generating RNA-targeted small molecules, ranging from fundamental chemistry to promising small molecule examples with demonstrated clinical efficacy. Specifically, we begin by exploring RNA functional classes, structural hierarchy, and dynamics. We then discuss fundamental RNA recognition principles along with methods for small molecule screening and RNA structure determination. Finally, we review unique challenges and emerging solutions from both the RNA and small molecule perspectives for generating RNA-targeted ligands before highlighting a selection of the "Greatest Hits" to date. These molecules target RNA in a variety of diseases, including cancer, neurodegeneration, and viral infection, in cellular and animal model systems. Additionally, we explore the recently FDA-approved small molecule regulator of RNA splicing, risdiplam, for treatment of spinal muscular atrophy. Together, this Tutorial Review showcases the fundamental role of chemical and molecular recognition principles in enhancing our understanding of RNA biology and contributing to the rapidly growing number of RNA-targeted probes and therapeutics. In particular, we hope this widely accessible review will serve as inspiration for aspiring small molecule and/or RNA researchers.
近年来，我们对 RNA 生物学的理解取得了一些进展，发现 RNA 在多种疾病状态中发挥着至关重要的作用，从病毒和细菌感染到癌症和神经紊乱等。因此，许多实验室都有兴趣开发针对 RNA 的类似药物的小分子。然而，这一发展带来了许多独特的挑战。例如，RNA 本质上是动态的，化学多样性有限。此外，在筛选过程中经常会发现具有混杂 RNA 结合配体的化合物。本综述概述了生成针对 RNA 的小分子的重要考虑因素和进展，范围从基础化学到具有临床疗效的有前途的小分子实例。具体来说，我们首先探讨 RNA 的功能类别、结构层次和动态。然后，我们讨论了基本的 RNA 识别原理，以及小分子筛选和 RNA 结构确定的方法。最后，我们综述了从 RNA 和小分子两个角度来看生成针对 RNA 的配体的独特挑战和新兴解决方案，然后重点介绍了迄今为止的“代表作”。这些分子在包括癌症、神经退行性疾病和病毒感染在内的多种疾病中靶向 RNA，在细胞和动物模型系统中均有应用。此外，我们还探讨了最近获得 FDA 批准的用于治疗脊髓性肌萎缩症的 RNA 剪接小分子调节剂 risdiplam。本综述展示了化学和分子识别原理在增强我们对 RNA 生物学的理解以及促进越来越多的针对 RNA 的探针和治疗药物方面的基本作用。特别是，我们希望这个广泛可用的综述能为有志于从事小分子和/或 RNA 研究的人提供灵感。
