Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.
J Med Chem. 2020 Sep 10;63(17):8880-8900. doi: 10.1021/acs.jmedchem.9b01927. Epub 2020 Mar 26.
RNA offers nearly unlimited potential as a target for small molecule chemical probes and lead medicines. Many RNAs fold into structures that can be selectively targeted with small molecules. This Perspective discusses molecular recognition of RNA by small molecules and highlights key enabling technologies and properties of bioactive interactions. Sequence-based design of ligands targeting RNA has established rules for affecting RNA targets and provided a potentially general platform for the discovery of bioactive small molecules. The RNA targets that contain preferred small molecule binding sites can be identified from sequence, allowing identification of off-targets and prediction of bioactive interactions by nature of ligand recognition of functional sites. Small molecule targeted degradation of RNA targets (ribonuclease-targeted chimeras, RIBOTACs) and direct cleavage by small molecules have also been developed. These growing technologies suggest that the time is right to provide small molecule chemical probes to target functionally relevant RNAs throughout the human transcriptome.
RNA 几乎可以作为小分子化学探针和先导药物的目标，提供无限的潜力。许多 RNA 折叠成可以与小分子选择性结合的结构。本文讨论了小分子对 RNA 的分子识别，并强调了生物活性相互作用的关键使能技术和特性。基于序列的配体设计靶向 RNA 已经为影响 RNA 靶标建立了规则，并为发现生物活性小分子提供了一个潜在的通用平台。可以从序列中识别包含首选小分子结合位点的 RNA 靶标，允许通过配体识别功能位点来识别非靶标并预测生物活性相互作用。还开发了 RNA 靶标的小分子靶向降解（核糖核酸酶靶向嵌合体，RIBOTACs）和小分子的直接切割。这些不断发展的技术表明，现在是时候为靶向整个人类转录组中功能相关 RNA 提供小分子化学探针了。
