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An Intrinsically Disordered Peptide Facilitates Non-Endosomal Cell Entry

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...

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Published in:Angewandte Chemie International Edition 2016-03, Vol.55 (10), p.3369-3372
Main Authors: Medina, Scott H., Miller, Stephen E., Keim, Allison I., Gorka, Alexander P., Schnermann, Martin J., Schneider, Joel P.
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cited_by cdi_FETCH-LOGICAL-c7778-d5a6af2d2b5232add2bcaa8da451cc95fb767ed4159d490e32db49d9553f483a3
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container_title Angewandte Chemie International Edition
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description 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. Disorder imparts order: CLIP6, an intrinsically disordered peptide, mediates cellular entry through non‐endosomal physical translocation across the membrane. This activity, defined by its unstructured state, facilitates the delivery of membrane‐impermeable cargo to the interior of cells.
doi_str_mv 10.1002/anie.201510518
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source Wiley-Blackwell Read & Publish Collection
subjects Amino Acid Sequence
Biocompatibility
Biomedical materials
Cargo
Cell permeability
cell-penetrating peptides
Cellular structure
Cytoplasm
Degradation
drug delivery
Drug delivery systems
Drug development
Endocytosis - physiology
Endosomes - metabolism
Entrapment
gene expression
Glutamic acid
Humans
Intracellular
Intrinsically Disordered Proteins - chemistry
Intrinsically Disordered Proteins - physiology
live-cell microscopy
Membranes
Peptides
Peptides - chemistry
Peptides - physiology
Permeability
Surface chemistry
Surgical implants
translocation
Transport
title An Intrinsically Disordered Peptide Facilitates Non-Endosomal Cell Entry
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