How We Think about Targeting RNA with Small Molecules
How We Think about Targeting RNA with Small Molecules
复制标题
如何用小分子靶向RNA
DOI：
10.1021/acs.jmedchem.9b01927
复制
发表时间：
2020-09-10
影响因子：
7.3
通讯作者：
Disney, Matthew D.
中科院分区：
文献类型：
--
作者：
Costales, Matthew G.;Childs-Disney, Jessica L.;Disney, Matthew D.
RNA作为小分子化学探针和先导药物的靶标提供了几乎无限的潜力。许多RNA折叠成可以选择性地与小分子靶向的结构。这一视角讨论了小分子对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RNA靶向配体设计已经建立了影响RNA靶标的规则，并为发现具有生物活性的小分子提供了一个潜在的通用平台。含有首选小分子结合位点的RNA靶标可以从序列中识别出来，从而可以通过配体识别功能位点的性质来识别靶外和预测生物活性相互作用。小分子靶向降解RNA靶标(核糖核酸酶靶向嵌合体，RIBOTAC)和小分子直接切割也已经开发出来。这些不断发展的技术表明，现在是时候提供小分子化学探针来靶向整个人类转录组中功能相关的RNA。
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.