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J Am Chem Soc. 2015 Feb 25;137(7):2536-2541. doi: 10.1021/ja510391n. Epub 2015 Feb 13.

Fluorescence correlation spectroscopy reveals highly efficient cytosolic delivery of certain penta-arg proteins and stapled peptides.

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Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06520-8107, United States.
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520-8107, United States.
Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States.
Contributed equally


We used fluorescence correlation spectroscopy (FCS) to accurately and precisely determine the relative efficiencies with which three families of "cell-penetrating peptides" traffic to the cytosol of mammalian cells. We find that certain molecules containing a "penta-arg" motif reach the cytosol, intact, with efficiencies greater than 50%. This value is at least 10-fold higher than that observed for the widely studied cationic sequence derived from HIV Tat or polyarginine Arg8, and equals that of hydrocarbon-stapled peptides that are active in cells and animals. Moreover, we show that the efficiency with which stapled peptides reach the cytosol, as determined by FCS, correlates directly with their efficacy in cell-based assays. We expect that these findings and the associated technology will aid the design of peptides, proteins, and peptide mimetics that predictably and efficiently reach the interior of mammalian cells.

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