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科学家将无活性的RNA结合小分子编程为生物活性降解剂
作者:小柯机器人 发布时间:2023/5/30 10:56:59


美国斯克里普斯研究所Matthew D. Disney等研究人员合作将无活性的RNA结合小分子编程为生物活性降解剂。2023年5月24日,国际知名学术期刊《自然》在线发表了这一成果。

研究人员报道了一个受自然产物启发的小分子集合和三维折叠的RNA结构之间的分子识别模式。在人类转录组中绘制了这些相互作用景观,并确定了结构-活性关系。尽管与功能位点结合的RNA结合化合物有望引起生物反应,但大多数确定的相互作用被预测为生物惰性的,因为它们结合在其他地方。研究人员推断,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结合分子被附加到一个杂环上,与RNase L结合并局部激活。

将RNase L的底物特异性与小分子的结合情况进行叠加,研究人员发现了许多有利的候选结合物,这些结合物在转化为降解剂时可能具有生物活性。研究人员提供了一个概念证明,为疾病相关的microRNA-155(pre-miR-155)的前体、JUN mRNA和MYC mRNA设计了选择性的降解剂。因此,小分子RNA靶向降解可以被用来将强大的、但不活跃的结合作用转化为RNA功能的有效和特定的调节剂。

据悉,靶标占用往往不足以引起生物活性,特别是对RNA而言,再加上围绕小分子对RNA结构的分子识别的长期挑战。

附:英文原文

Title: Programming inactive RNA-binding small molecules into bioactive degraders

Author: 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.

Issue&Volume: 2023-05-24

Abstract: 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 L1. 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.

DOI: 10.1038/s41586-023-06091-8

Source: https://www.nature.com/articles/s41586-023-06091-8

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html