title: The tetrapeptide core of the carrier peptide Xentry is cell-penetrating: novel activatable forms of Xentry.
abstract: Here we describe a structure-function analysis of the cell-penetrating peptide Xentry derived from the X-protein of the hepatitis B virus. Remarkably, the tetrapeptide core LCLR retains the cell-penetrating ability of the parental peptide LCLRPVG, as either an L- or D-enantiomer. Substitution of the cysteine with leucine revealed that the cysteine is essential for activity. In contrast, the C-terminal arginine could be substituted in the L-isomer with lysine, histidine, glutamic acid, glutamine, and asparagine, though the resulting peptides displayed distinct cell-type-specific uptake. Substitution of the leucines in the D-isomer with other hydrophobic residues revealed that leucines are optimal for activity. Surprisingly, linear di- and tetra-peptide forms of Xentry are not cell-permeable. Protease-activatable forms of Xentry were created by fusing Xentry to itself via a protease-cleavable peptide, or by attaching a heparin mimic peptide to the N-terminus. These novel activatable forms of Xentry were only taken up by MCF-7 cells after cleavage by matrix metalloproteinase 9, and could be used to deliver drugs specifically to tumours.
authors.affiliation: Department of Molecular Medicine & Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1005, New Zealand.
authors.forename: Kristopher
authors.initials: K
authors.lastname: Montrose
authors.affiliation: Department of Molecular Medicine & Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1005, New Zealand.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Molecular Medicine & Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1005, New Zealand.
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Krissansen
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D020014:K562 Cells; D061986:MCF-7 Cells; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D057846:Cell-Penetrating Peptides; D009842:Oligopeptides; D020780:Matrix Metalloproteinase 9