Identification and characterization of a new family of cell penetrating peptides: Cyclic cell penetrating peptides

Cascales, Laura, Henriques, Sónia T., Kerr, Markus C., Huang, Yen-Hua, Sweet, Matthew J., Daly, Norelle L. and Craik, David J. (2011) Identification and characterization of a new family of cell penetrating peptides: Cyclic cell penetrating peptides. Journal of Biological Chemistry, Epub ahead of print 42: 36932-36943. doi:10.1074/jbc.M111.264424

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Author Cascales, Laura
Henriques, Sónia T.
Kerr, Markus C.
Huang, Yen-Hua
Sweet, Matthew J.
Daly, Norelle L.
Craik, David J.
Title Identification and characterization of a new family of cell penetrating peptides: Cyclic cell penetrating peptides
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2011
Sub-type Article (original research)
DOI 10.1074/jbc.M111.264424
Open Access Status File (Publisher version)
Volume Epub ahead of print
Issue 42
Start page 36932
End page 36943
Total pages 13
Place of publication United States
Publisher American Society for Biochemistry and Molecular Biology, Inc.
Collection year 2012
Language eng
Abstract Cell-penetrating peptides (CPPs) translocate across the plasma membrane of living cells and are potentially useful agents in drug delivery applications. Disulfide-rich cyclic peptides also have promise in drug design because of their exceptional stability, but to date only one cyclic peptide has been reported to penetrate cells, the Momordica cochinchinensis trypsin inhibitor II (MCoTI-II). MCoTI-II belongs to the cyclotide family of plant-derived cyclic peptides that are characterized by a cyclic cystine knot motif. Previous studies in fixed cells showed that MCoTI-II could penetrate cells but kalata B1, a prototypic cyclotide from a separate subfamily of cyclotides, was bound to the plasma membrane and did not translocate into cells. Here we show by live cell imaging that both MCoTI-II and kalata B1 enter cells. Kalata B1 has the same cyclic cystine knot structural motif as MCoTI-II, but differs in sequence, and the mechanism by which these two peptides enter cells also differs. MCoTI-II enters via macropinocytosis, mediated by interaction of positively charged residues with phosphoinositides in the cell membrane, whereas kalata B1 interacts directly with the membrane by targeting phosphatidyl-ethanolamine phospholipids, leading to membrane bending and vesicle formation. We also show that another plant-derived cyclic peptide, SFTI-1, can penetrate cells. SFTI-1 comprises just 14 amino acids and, with the exception of its cyclic backbone, is structurally different from the cyclotides. SFTI-1 did not interact with any of the phospholipids tested and its mechanism of penetration appears to be distinct from MCoTI-II and kalata B1. The ability of diverse disulfide-rich, cyclic peptides to penetrate cells enhances their potential in drug design, and we propose a new classification for them, i.e. cyclic cell-penetrating peptides (CCPPs).
Keyword Biophysics
Cell permeabilization
Cell-penetrating peptides
Peptide interactions
Peptide transport
Cyclic peptides
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Chemistry and Molecular Biosciences
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Citation counts: TR Web of Science Citation Count  Cited 65 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 11 Oct 2011, 13:49:17 EST by Matt Sweet on behalf of School of Chemistry & Molecular Biosciences