An Intrinsically Disordered Peptide Facilitates Non-Endosomal Cell Entry

Angewandte Chemie
Scott H MedinaJoel P Schneider

Abstract

Many cell-penetrating peptides (CPPs) fold at cell surfaces, adopting α- or β-structure that enable their intracellular transport. However, the same structural folds that facilitate cellular entry can also elicit potent membrane-lytic activity, limiting their use in delivery applications. Further, a distinct CPP can enter cells through many mechanisms, often leading to endosomal entrapment. Herein, we describe an intrinsically disordered peptide (CLIP6) that exclusively employs non-endosomal mechanisms to cross cellular membranes, while being remarkably biocompatible and serum-stable. We show that a single anionic glutamate residue is responsible for maintaining the disordered bioactive state of the peptide, defines its mechanism of cellular entry, and is central to its biocompatibility. CLIP6 can deliver membrane-impermeable cargo directly to the cytoplasm of cells, suggesting its broad utility for delivery of drug candidates limited by poor cell permeability and endosomal degradation.

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Citations

Jan 24, 2017·Advanced Materials·Xiao-Qiu Dou, Chuan-Liang Feng
Jul 10, 2018·Biochemistry and Molecular Biology Education : a Bimonthly Publication of the International Union of Biochemistry and Molecular Biology·Sabine ReißerAnne S Ulrich
Sep 5, 2018·Chembiochem : a European Journal of Chemical Biology·Alejandro Méndez-ArdoyJavier Montenegro
Jan 9, 2020·Nanoscale·Xinxin LiZhimou Yang
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Feb 8, 2018·Biomaterials Science·Xiao-Jiao DuJun Wang
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Apr 17, 2021·Nature Chemistry·Anselm F L SchneiderChristian P R Hackenberger
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Dec 7, 2017·Bioconjugate Chemistry·Terese SoudahEylon Yavin
Sep 25, 2019·Bioconjugate Chemistry·Huaimin WangBing Xu

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