Early Endosomal Escape of a Cyclic Cell-Penetrating Peptide Allows Effective Cytosolic Cargo Delivery

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Publication Details

Author list: Qian ZQ, LaRochelle JR, Jiang BS, Lian WL, Hard RL, Selner NG, Luechapanichkul R, Barrios AM, Pei DH
Publisher: American Chemical Society
Publication year: 2014
Volume number: 53
Issue number: 24
Start page: 4034
End page: 4046
Number of pages: 13
ISSN: 0006-2960
Languages: English-Great Britain (EN-GB)


Cyclic heptapeptide cyclo(F Phi RRRRQ) (cF Phi R-4, where Phi is L-2-naphthylalanine) was recently found to be efficiently internalized by mammalian cells. In this study, its mechanism of internalization was investigated by perturbing various endocytic events through the introduction of pharmacologic agents and genetic mutations. The results show that cF Phi R4 binds directly to membrane phospholipids, is internalized into human cancer cells through endocytosis, and escapes from early endosomes into the cytoplasm. Its cargo capacity was examined with a wide variety of molecules, including small-molecule dyes, linear and cyclic peptides of various charged states, and proteins. Depending on the nature of the cargos, they may be delivered by endocyclic (insertion of cargo into the cF Phi R-4 ring), exocyclic (attachment of cargo to the Gin side chain), or bicyclic approaches (fusion of cF Phi R-4 and cyclic cargo rings). The overall delivery efficiency (i.e., delivery of cargo into the cytoplasm and nucleus) of cF Phi R-4, was 4-12-fold higher than those of nonaarginine, HIV Tat-derived peptide, or penetratin. The higher delivery efficiency, coupled with superior serum stability, minimal toxicity, and synthetic accessibility, renders cF Phi R-4 a useful transporter for intracellular cargo delivery and a suitable system for investigating the mechanism of endosomal escape.


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Last updated on 2019-23-08 at 11:15