AUTACs: Cargo-Specific Degraders Using Selective Autophagy
AUTACs: Cargo-Specific Degraders Using Selective Autophagy
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DOI：
10.1016/j.molcel.2019.09.009
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发表时间：
2019-12-05
期刊：
影响因子：
16
通讯作者：
Arimoto, Hirokazu
中科院分区：
文献类型：
--
作者：
Takahashi, Daiki;Moriyama, Jun;Arimoto, Hirokazu
蛋白质沉默是生物医学研究中的重要工具。以PROTAC为代表的靶向蛋白降解（TPD）策略正迅速成为药物发现的模式。然而，目前的TPD技术的范围是有限的，因为许多细胞内的材料不是蛋白酶体清除的底物。在这里，我们描述了一种新的靶向清除策略（自噬靶向嵌合体[AUTAC]），它包含一个降解标签（鸟嘌呤衍生物）和一个弹头，以提供靶向特异性。正如自噬的底物范围所预期的那样，AUTAC降解了片段化的线粒体以及蛋白质。线粒体靶向的AUTAC加速了患者来源的成纤维细胞中功能失调的碎片化线粒体的去除和功能正常的线粒体的生物合成。还观察到对急性线粒体损伤的细胞保护作用。典型的自噬被认为是一种非选择性的大量分解系统，并且没有一种可用的自噬诱导剂表现出有用的货物选择性。由于其靶点特异性，AUTAC为基于自噬的药物研究提供了一种新的模式。
Protein silencing represents an essential tool in biomedical research. Targeted protein degradation (TPD) strategies exemplified by PROTACs are rapidly emerging as modalities in drug discovery. However, the scope of current TPD techniques is limited because many intracellular materials are not substrates of proteasomal clearance. Here, we described a novel targeted-clearance strategy (autophagy-targeting chimera [AUTAC]) that contains a degradation tag (guanine derivatives) and a warhead to provide target specificity. As expected from the substrate scope of autophagy, AUTAC degraded fragmented mitochondria as well as proteins. Mitochondria-targeted AUTAC accelerated both the removal of dysfunctional fragmented mitochondria and the biogenesis of functionally normal mitochondria in patient-derived fibroblast cells. Cytoprotective effects against acute mitochondrial injuries were also seen. Canonical autophagy is viewed as a nonselective bulk decomposition system, and none of the available autophagy-inducing agents exhibit useful cargo selectivity. With its target specificity, AUTAC provides a new modality for research on autophagy-based drugs.