Department of Chemistry, University of California, Riverside, California 92521, United States.
Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, United States.
J Am Chem Soc. 2022 Nov 9;144(44):20288-20297. doi: 10.1021/jacs.2c07420. Epub 2022 Oct 27.
Delivering cargo molecules across the plasma membrane is critical for biomedical research, and the need to develop molecularly well-defined tags that enable cargo transportation is ever-increasing. We report here a hydrophilic endocytosis-promoting peptide (EPP6) rich in hydroxyl groups with no positive charge. EPP6 can transport a wide array of small-molecule cargos into a diverse panel of animal cells. Mechanistic studies revealed that it entered the cells through a caveolin- and dynamin-dependent endocytosis pathway, mediated by the surface receptor fibrinogen C domain-containing protein 1. After endocytosis, EPP6 trafficked through early and late endosomes within 30 min. Over time, EPP6 partitioned among cytosol, lysosomes, and some long-lived compartments. It also demonstrated prominent transcytosis abilities in both and models. Our study proves that positive charge is not an indispensable feature for hydrophilic cell-penetrating peptides and provides a new category of molecularly well-defined delivery tags for biomedical applications.
将货物分子递送到质膜对于生物医学研究至关重要，因此越来越需要开发出具有明确分子结构的标签来实现货物运输。我们在此报告了一种富含羟基且不带正电荷的亲水性内吞促进肽（EPP6）。EPP6 可以将各种小分子货物运输到多种动物细胞中。机制研究表明，它通过 caveolin 和 dynamin 依赖性内吞作用途径进入细胞，该途径由表面受体纤维蛋白原 C 结构域包含蛋白 1 介导。内吞后，EPP6 在 30 分钟内通过早期和晚期内涵体运输。随着时间的推移，EPP6 在细胞质、溶酶体和一些长寿隔室之间分配。它还在 和 模型中表现出明显的转胞吞作用能力。我们的研究证明，正电荷对于亲水性细胞穿透肽不是必不可少的特征，并为生物医学应用提供了一类新的具有明确分子结构的递药标签。
