Efficient Delivery of Cyclic Peptides into Mammalian Cells with Short Sequence Motifs Ziqing Qian Tao Liu Yu-Yu Liu Roger Briesewitz Amy M. Barrios Sissy M. Jhiang Dehua Pei 10.1021/cb3005275.s001 https://acs.figshare.com/articles/journal_contribution/Efficient_Delivery_of_Cyclic_Peptides_into_Mammalian_Cells_with_Short_Sequence_Motifs/2442649 Cyclic peptides hold great potential as therapeutic agents and research tools, but their broad application has been limited by poor membrane permeability. Here, we report a potentially general approach for intracellular delivery of cyclic peptides. Short peptide motifs rich in arginine and hydrophobic residues (e.g., FΦRRRR, where Φ is l-2-naphthylalanine), when embedded into small- to medium-sized cyclic peptides (7–13 amino acids), bound to the plasma membrane of mammalian cultured cells and were subsequently internalized by the cells. Confocal microscopy and a newly developed peptide internalization assay demonstrated that cyclic peptides containing these transporter motifs were translocated into the cytoplasm and nucleus at efficiencies 2–5-fold higher than that of nonaarginine (R<sub>9</sub>). Furthermore, incorporation of the FΦRRRR motif into a cyclic peptide containing a phosphocoumaryl aminopropionic acid (pCAP) residue generated a cell permeable, fluorogenic probe for detecting intracellular protein tyrosine phosphatase activities. 2013-02-15 00:00:00 phosphocoumaryl aminopropionic acid intracellular protein tyrosine phosphatase activities cyclic peptides F ΦRRRR motif Short Sequence MotifsCyclic peptides peptide internalization assay Short peptide motifs