Enzymatic Cleavage of Branched Peptides for Targeting Mitochondria,Journal of the American Chemical Society

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Enzymatic Cleavage of Branched Peptides for Targeting Mitochondria
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2018-01-19 , DOI: 10.1021/jacs.7b11582
Hongjian He ₁ , Jiaqing Wang ₁ , Huaimin Wang ₁ , Ning Zhou ₁ , Dongsik Yang ₁ , Douglas R Green ₂ , Bing Xu ₁

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Most of the reported mitochondria-targeting molecules are lipophilic and cationic, and thus they may become cytotoxic with accumulation. Here we show enzymatic cleavage of branched peptides that carry negative charges for targeting mitochondria. Conjugating a well-established protein tag (i.e., FLAG-tag) to self-assembling motifs affords the precursors that form micelles. Enzymatic cleavage of the hydrophilic FLAG motif (DDDDK) by enterokinase (ENTK) turns the micelles to nanofibers. After being taken up by cells, the micelles, upon the action of intracellular ENTK, turn into nanofibers to locate mainly at mitochondria. The micelles of the precursors are able to deliver cargos (either small molecules or proteins) into cells, largely to mitochondria and within 2 h. Preventing ENTK proteolysis diminishes mitochondria targeting. As the first report of using enzymatic self-assembly for targeting mitochondria and delivery cargos to mitochondria, this work illustrates a fundamentally new way to target subcellular organelles for biomedicine.

中文翻译：

用于靶向线粒体的支链肽的酶促切割

大多数报道的线粒体靶向分子是亲脂性和阳离子的，因此它们可能随着积累而变得具有细胞毒性。在这里，我们展示了带有负电荷以靶向线粒体的支链肽的酶裂解。将完善的蛋白质标签（即 FLAG 标签）与自组装基序缀合可提供形成胶束的前体。肠激酶 (ENTK) 对亲水性 FLAG 基序 (DDDDK) 进行酶裂解，将胶束转变为纳米纤维。胶束被细胞摄取后，在细胞内ENTK的作用下，变成纳米纤维，主要定位于线粒体。前体的胶束能够在 2 小时内将货物（小分子或蛋白质）输送到细胞中，主要输送到线粒体。防止 ENTK 蛋白水解会减少线粒体靶向。作为第一份使用酶自组装靶向线粒体并将货物递送至线粒体的报告，这项工作阐明了一种用于生物医学的靶向亚细胞细胞器的全新方法。

更新日期：2018-01-19

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