Programming inactive RNA-binding small molecules into bioactive degraders.
Programming inactive RNA-binding small molecules into bioactive degraders.
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DOI：
10.1038/s41586-023-06091-8
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发表时间：
2023-06
期刊：
影响因子：
64.8
通讯作者：
Disney, Matthew D.
中科院分区：
文献类型：
--
作者：
Tong, Yuquan;Lee, Yeongju;Liu, Xiaohui;Childs-Disney, Jessica L.;Suresh, Blessy M.;Benhamou, Raphael I.;Yang, Chunying;Li, Weimin;Costales, Matthew G.;Haniff, Hafeez S.;Sievers, Sonja;Abegg, Daniel;Wegner, Tristan;Paulisch, Tiffany O.;Lekah, Elizabeth;Grefe, Maison;Crynen, Gogce;Van Meter, Montina;Wang, Tenghui;Gibaut, Quentin M. R.;Cleveland, John L.;Adibekian, Alexander;Glorius, Frank;Waldmann, Herbert;Disney, Matthew D.
靶标占据通常不足以引发生物活性，特别是对于RNA，由于围绕小分子对RNA结构的分子识别的长期挑战而加剧。在这里，我们研究了自然产物启发的小分子集合和三维折叠RNA结构之间的分子识别模式。在人类转录组中绘制这些相互作用景观定义了结构-活性关系。虽然结合到功能位点的RNA结合化合物预计会引起生物反应，但大多数确定的相互作用预计是生物惰性的，因为它们结合在其他地方。我们推断，对于这种情况，调节RNA生物学的另一种策略是通过核糖核酸酶靶向嵌合体切割靶标，其中RNA结合分子附加到结合并局部激活RNA酶L的杂环上。RNA酶L的底物特异性与小分子结合景观的叠加揭示了许多有利的候选结合剂，当转化为降解剂时，这些结合剂可能具有生物活性。我们提供了一个概念验证，设计了疾病相关microRNA-155（pre-miR-155），JUN mRNA和MYC mRNA的前体的选择性降解剂。因此，可以利用小分子RNA靶向降解将强但无活性的结合相互作用转化为RNA功能的有效和特异性调节剂。小分子RNA靶向降解可用于将强而无活性的结合相互作用转化为RNA功能的有效和特异性调节剂。
Target occupancy is often insufficient to elicit biological activity, particularly for RNA, compounded by the longstanding challenges surrounding the molecular recognition of RNA structures by small molecules. Here we studied molecular recognition patterns between a natural-product-inspired small-molecule collection and three-dimensionally folded RNA structures. Mapping these interaction landscapes across the human transcriptome defined structure–activity relationships. Although RNA-binding compounds that bind to functional sites were expected to elicit a biological response, most identified interactions were predicted to be biologically inert as they bind elsewhere. We reasoned that, for such cases, an alternative strategy to modulate RNA biology is to cleave the target through a ribonuclease-targeting chimera, where an RNA-binding molecule is appended to a heterocycle that binds to and locally activates RNase L. Overlay of the substrate specificity for RNase L with the binding landscape of small molecules revealed many favourable candidate binders that might be bioactive when converted into degraders. We provide a proof of concept, designing selective degraders for the precursor to the disease-associated microRNA-155 (pre-miR-155), JUN mRNA and MYC mRNA. Thus, small-molecule RNA-targeted degradation can be leveraged to convert strong, yet inactive, binding interactions into potent and specific modulators of RNA function. Small-molecule RNA-targeted degradation can be leveraged to convert strong, yet inactive, binding interactions into potent and specific modulators of RNA function.
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