title: Discovery and Mechanism of Highly Efficient Cyclic Cell-Penetrating Peptides.
abstract: Previous cell-penetrating peptides (CPPs) generally have low cytosolic delivery efficiencies, because of inefficient endosomal escape. In this study, a family of small, amphipathic cyclic peptides was found to be highly efficient CPPs, with cytosolic delivery efficiencies of up to 120% (compared to 2.0% for Tat). These cyclic CPPs bind directly to the plasma membrane phospholipids and enter mammalian cells via endocytosis, followed by efficient release from the endosome. Their total cellular uptake efficiency correlates positively with the binding affinity for the plasma membrane, whereas their endosomal escape efficiency increases with the endosomal membrane-binding affinity. The cyclic CPPs induce membrane curvature on giant unilamellar vesicles and budding of small vesicles, which subsequently collapse into amorphous lipid/peptide aggregates. These data suggest that cyclic CPPs exit the endosome by binding to the endosomal membrane and inducing CPP-enriched lipid domains to bud off as small vesicles. Together with their high proteolytic stability, low cytotoxicity, and oral bioavailability, these cyclic CPPs should provide a powerful system for intracellular delivery of therapeutic agents and chemical probes.
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University , 484 West 12th Avenue, Columbus, Ohio 43210, United States.
authors.forename: Ziqing
authors.initials: Z
authors.lastname: Qian
authors.affiliation: School of Biosciences, University of Kent , Canterbury, CT2 7NJ, United Kingdom.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Martyna
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University , 484 West 12th Avenue, Columbus, Ohio 43210, United States.
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Hard
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University , 484 West 12th Avenue, Columbus, Ohio 43210, United States.
authors.forename: George
authors.initials: G
authors.lastname: Appiah-Kubi
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Coss
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Mitch A
authors.initials: MA
authors.lastname: Phelps
authors.affiliation: School of Biosciences, University of Kent , Canterbury, CT2 7NJ, United Kingdom.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Rossman
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University , 484 West 12th Avenue, Columbus, Ohio 43210, United States.
authors.forename: Dehua
authors.initials: D
authors.lastname: Pei
mesh_terms: D000072283:A549 Cells; D000818:Animals; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011992:Endosomes / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010539:Permeability
chemical_list: D057846:Cell-Penetrating Peptides; D010456:Peptides, Cyclic