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Affecting RNA biology genome-wide by binding small molecules and chemically induced proximity.
Current opinion in chemical biology Pub Date : 2021-06-09 , DOI: 10.1016/j.cbpa.2021.03.006
Jared T Baisden 1 , Jessica L Childs-Disney 1 , Lucas S Ryan 1 , Matthew D Disney 1
Affiliation  

The ENCODE and genome-wide association projects have shown that much of the genome is transcribed into RNA and much less is translated into protein. These and other functional studies suggest that the druggable transcriptome is much larger than the druggable proteome. This review highlights approaches to define druggable RNA targets and structure-activity relationships across genomic RNA. Binding compounds can be identified and optimized into structure-specific ligands by using sequence-based design with various modes of action, for example, inhibiting translation or directing pre-mRNA splicing outcomes. In addition, strategies to direct protein activity against an RNA of interest via chemically induced proximity is a burgeoning area that has been validated both in cells and in preclinical animal models, and we describe that it may allow rapid access to new avenues to affect RNA biology. These approaches and the unique modes of action suggest that more RNAs are potentially amenable to targeting than proteins.

中文翻译:

通过结合小分子和化学诱导的接近来影响全基因组的 RNA 生物学。

ENCODE 和全基因组关联项目表明,大部分基因组被转录成 RNA,很少被翻译成蛋白质。这些和其他功能研究表明,可药物转录组比可药物蛋白质组大得多。这篇综述重点介绍了定义可药物化 RNA 靶点和跨基因组 RNA 的结构-活性关系的方法。通过使用基于序列的设计和各种作用模式,例如抑制翻译或指导前 mRNA 剪接结果,可以识别结合化合物并将其优化为结构特异性配体。此外,通过化学诱导接近来引导蛋白质活性针对感兴趣的RNA的策略是一个新兴领域,已在细胞和临床前动物模型中得到验证,我们描述它可能允许快速获得影响RNA生物学的新途径。这些方法和独特的作用模式表明,与蛋白质相比,更多的 RNA 可能适合靶向。
更新日期:2021-06-09
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