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The tetrapeptide core of the carrier peptide Xentry is cell-penetrating: novel activatable forms of Xentry

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...

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Autores principales: Montrose, Kristopher, Yang, Yi, Krissansen, Geoffrey W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014984/
https://www.ncbi.nlm.nih.gov/pubmed/24811205
http://dx.doi.org/10.1038/srep04900
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author Montrose, Kristopher
Yang, Yi
Krissansen, Geoffrey W.
author_facet Montrose, Kristopher
Yang, Yi
Krissansen, Geoffrey W.
author_sort Montrose, Kristopher
collection PubMed
description 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.
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spelling pubmed-40149842014-05-13 The tetrapeptide core of the carrier peptide Xentry is cell-penetrating: novel activatable forms of Xentry Montrose, Kristopher Yang, Yi Krissansen, Geoffrey W. Sci Rep Article 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. Nature Publishing Group 2014-05-09 /pmc/articles/PMC4014984/ /pubmed/24811205 http://dx.doi.org/10.1038/srep04900 Text en Copyright © 2014, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by/3.0/ This work is licensed under a Creative Commons Attribution 3.0 Unported License. The images in this article are included in the article's Creative Commons license, unless indicated otherwise in the image credit; if the image is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the image. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/
spellingShingle Article
Montrose, Kristopher
Yang, Yi
Krissansen, Geoffrey W.
The tetrapeptide core of the carrier peptide Xentry is cell-penetrating: novel activatable forms of Xentry
title The tetrapeptide core of the carrier peptide Xentry is cell-penetrating: novel activatable forms of Xentry
title_full The tetrapeptide core of the carrier peptide Xentry is cell-penetrating: novel activatable forms of Xentry
title_fullStr The tetrapeptide core of the carrier peptide Xentry is cell-penetrating: novel activatable forms of Xentry
title_full_unstemmed The tetrapeptide core of the carrier peptide Xentry is cell-penetrating: novel activatable forms of Xentry
title_short The tetrapeptide core of the carrier peptide Xentry is cell-penetrating: novel activatable forms of Xentry
title_sort tetrapeptide core of the carrier peptide xentry is cell-penetrating: novel activatable forms of xentry
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014984/
https://www.ncbi.nlm.nih.gov/pubmed/24811205
http://dx.doi.org/10.1038/srep04900
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