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Biochemistry. 2016 May 10;55(18):2601-12. doi: 10.1021/acs.biochem.6b00226. Epub 2016 Apr 28.

Discovery and Mechanism of Highly Efficient Cyclic Cell-Penetrating Peptides.

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Department of Chemistry and Biochemistry, The Ohio State University , 484 West 12th Avenue, Columbus, Ohio 43210, United States.
School of Biosciences, University of Kent , Canterbury, CT2 7NJ, United Kingdom.
Division of Pharmaceutics, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.


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.

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