RNA‐PROTACs: Degraders of RNA‐Binding Proteins,Angewandte Chemie International Edition

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RNA‐PROTACs: Degraders of RNA‐Binding Proteins
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2020-10-27 , DOI: 10.1002/anie.202012330
Alice Ghidini ₁ , Antoine Cléry ₂ , François Halloy ₁ , Frédéric H T Allain ₂ , Jonathan Hall ₁

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Defects in the functions of RNA binding proteins (RBPs) are at the origin of many diseases; however, targeting RBPs with conventional drugs has proven difficult. PROTACs are a new class of drugs that mediate selective degradation of a target protein through a cell's ubiquitination machinery. PROTACs comprise a moiety that binds the selected protein, conjugated to a ligand of an E3 ligase. Herein, we introduce RNA‐PROTACs as a new concept in the targeting of RBPs. These chimeric structures employ small RNA mimics as targeting groups that dock the RNA‐binding site of the RBP, whereupon a conjugated E3‐recruiting peptide derived from the HIF‐1α protein directs the RBP for proteasomal degradation. We performed a proof‐of‐concept demonstration with the degradation of two RBPs—a stem cell factor LIN28 and a splicing factor RBFOX1—and showed their use in cancer cell lines. The RNA‐PROTAC approach opens the way to rapid, selective targeting of RBPs in a rational and general fashion.

中文翻译：

RNA-PROTAC：RNA 结合蛋白的降解剂

RNA 结合蛋白 (RBP) 功能缺陷是许多疾病的根源；然而，事实证明，用传统药物靶向 RBP 是很困难的。 PROTAC 是一类新型药物，可通过细胞的泛素化机制介导靶蛋白的选择性降解。 PROTAC 包含结合所选蛋白质的部分，并与 E3 连接酶的配体缀合。在此，我们引入 RNA-PROTAC 作为 RBP 靶向的新概念。这些嵌合结构采用小 RNA 模拟物作为靶向基团，与 RBP 的 RNA 结合位点对接，随后源自 HIF-1α 蛋白的缀合 E3 募集肽指导 RBP 进行蛋白酶体降解。我们对两种 RBP（干细胞因子 LIN28 和剪接因子 RBFOX1）的降解进行了概念验证演示，并展示了它们在癌细胞系中的用途。 RNA-PROTAC 方法为以合理且通用的方式快速、选择性地靶向 RBP 开辟了道路。

更新日期：2020-10-27

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