Azo-PROTAC: Novel Light-Controlled Small-Molecule Tool for Protein Knockdown
Azo-PROTAC: Novel Light-Controlled Small-Molecule Tool for Protein Knockdown
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Azo-PROTAC：用于蛋白质敲低的新型光控小分子工具
DOI：
10.1021/acs.jmedchem.9b02058
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发表时间：
2020-05-14
影响因子：
7.3
通讯作者：
Jiang, Zheng-Yu
中科院分区：
文献类型：
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作者：
Jin, Yu-Hui;Lu, Meng-Chen;Jiang, Zheng-Yu
可逆地改变内源性蛋白质水平是持续存在的问题。在此，我们设计了光开关偶氮苯-蛋白水解靶向嵌合体（Azo-PROTAC），通过在E3连接酶和目标蛋白质的配体之间包括偶氮苯部分。偶氮PROTAC是用于细胞中蛋白质敲除的光控小分子工具。光诱导的构象变化可以转换活性状态以诱导蛋白质降解活性，这可以通过完整细胞中的光暴露来控制。我们比较了具有不同构型和接头长度的Azo-PROTAC的蛋白质降解能力。使用对骨髓性白血病K562细胞中的BCR-ABL融合蛋白和ABL蛋白具有最佳降解能力的稳定形式，我们表明Azo-PROTAC将小分子PROTAC的有效蛋白质敲除和容易的细胞摄取特性与可逆的光开关能力相结合，提供了一种基于光诱导的可逆开/关特性的有前途的化学敲除策略。
Reversibly altering endogenous protein levels are persistent issues. Herein, we designed photoswitchable azobenzene-proteolysis targeting chimeras (Azo-PROTACs) by including azobenzene moieties between ligands for the E3 ligase and the protein of interest. Azo-PROTACs are light-controlled small-molecule tools for protein knockdown in cells. The light-induced configuration change can switch the active state to induce protein degradation activity, which can be reversely controlled by light exposure in intact cells. We compared the protein degradation abilities of Azo-PROTACs with different configurations and linker lengths. Using the stable form with the best degradation ability against the BCR-ABL fusion and ABL proteins in myelogenous leukemia K562 cells, we showed that Azo-PROTAC combines the potent protein knockdown and facile cell uptake properties of the small-molecule PROTAC with a reversible photoswitchability, offering a promising chemical knockdown strategy based on the light-induced reversible on/off properties.