Mitochondria-targeted delivery methods offer a straightforward approach for studying mitochondria-related diseases and potentially streamlining therapeutic development. Peptoids (oligo-N-substituted glycines) are biocompatible peptidomimetics that display similar physicochemical properties as peptides with the added advantage of enhanced resistance to proteolytic cleavage. In particular, amphipathic peptoids are membrane-permeable and their cationic charges and hydrophobicity can be readily modified for specific purposes, such as cell penetration, anti-cancer or antibacterial activity. Previously, we identified a series of amphipathic peptoids that showed efficient cell penetration and mitochondrial localization. As a continued effort to identify selective mitochondrial transporters, we designed new analogs with varying hydrophobicity and net charges. We observed that overall increase in hydrophobicity did not result in enhanced mitochondrial localization while maintaining high cell permeability. Moreover, a certain degree of a positive net charge was critical for mitochondrial localization. In conclusion, our mitochondria-targeting peptoids provide a highly selective and robust delivery system for bioactive molecules.

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具有不同疏水性和阳离子电荷的线粒体靶向拟肽的合成及构效关系

线粒体靶向递送方法为研究线粒体相关疾病和潜在地简化治疗开发提供了一种直接的方法。拟肽（寡-N-取代的甘氨酸）是生物相容的肽模拟物，其表现出与肽相似的物理化学性质，并具有增强的对蛋白水解切割的抗性的额外优势。特别是，两亲性拟肽是可渗透膜的，并且它们的阳离子电荷和疏水性可以很容易地为特定目的而改变，例如细胞穿透、抗癌或抗菌活性。以前，我们确定了一系列显示有效的细胞穿透和线粒体定位的两亲 peptoids。作为识别选择性线粒体转运蛋白的持续努力，我们设计了具有不同疏水性和净电荷的新类似物。我们观察到疏水性的整体增加不会导致线粒体定位增强，同时保持高细胞通透性。而且，一定程度的正净电荷对线粒体定位至关重要。总之，我们的线粒体靶向类肽为生物活性分子提供了一个高度选择性和强大的递送系统。