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.

靶点占据通常不足以引发生物活性，特别是对于 RNA，而小分子对 RNA 结构的分子识别长期存在的挑战更是雪上加霜。在这里，我们研究了天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。将这些相互作用景观映射到人类转录组定义的结构-活性关系中。尽管与功能位点结合的RNA结合化合物预计会引发生物反应，但大多数已识别的相互作用预计在生物上是惰性的，因为它们与其他地方结合。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 RNase L ¹的杂环上。 RNase L 的底物特异性与小分子的结合图谱的叠加揭示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。我们提供了概念验证，为疾病相关的 microRNA-155 (pre-miR-155)、 JUN mRNA 和MYC mRNA 的前体设计选择性降解剂。因此，可以利用小分子 RNA 靶向降解将强但不活跃的结合相互作用转化为有效且特异性的 RNA 功能调节剂。