An Intrinsically Disordered Peptide Facilitates Non-Endosomal Cell Entry

• Published in: Angewandte Chemie Vol. 128; no. 10; pp. 3430 - 3433
• Main Authors: Medina, Scott H., Miller, Stephen E., Keim, Allison I., Gorka, Alexander P., Schnermann, Martin J., Schneider, Joel P.
• Format: Journal Article
• Language: English; German
• Published: Weinheim Blackwell Publishing Ltd 01.03.2016; Wiley Subscription Services, Inc
• Subjects: Biocompatibility; Biomedical materials; Cargo; Cell permeability; Cellular; Cellular structure; Chemistry; Constraining; Cytoplasm; Degradation; Drug delivery systems; Drug development; Drugs; Entrapment; Genexpression; Glutamic acid; Intracellular; Membranes; Peptides; Permeability; Surface chemistry; Surgical implants; Translokation; Transport; Wirkstofftransport; Zellgängige Peptide; Zellmikroskopie
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201510518

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. Fehlgeordnete Verhältnisse: Das intrinsisch fehlgeordnete Peptid CLIP6 vermittelt den Eintritt in Zellen durch ein nichtendosomales physikalisches Überwinden der Membran. Diese Aktivität ist eine Folge des nichtstrukturierten Zustands; sie erleichtert den Transport ansonsten nicht membranpermeierender Substanzen in das Zellinnere.