Protein transduction domains (PTDs), both naturally occurring and synthetic, have been increasingly employed to deliver biologically active agents to a variety of cell types in vitro and in vivo. In addition to the previously characterized arginine-rich PTDs, including Tat (transactivator of transcription), Antp (Antennapedia) and PTD-5, we have demonstrated that lysine and ornithine, as well as arginine, homopolymers are able to mediate transduction of a wide variety of agents. To screen for optimal PTDs, we have used as a therapeutic cargo a peptide derived from IKK {IκB [inhibitor of NF-κB (nuclear factor κB)] kinase} β, able to bind to the IKK regulatory subunit [NEMO (NF-κB essential modulator)], preventing formation of an active kinase complex. This peptide, termed NBD, is able to block activation of NF-κB, but not basal activity. We demonstrate that PTD-mediated delivery of NBD using certain PTDs, in particular 8K (octalysine), is therapeutic following systemic delivery in murine models of inflammatory bowel disease, diabetes and muscular dystrophy. In addition, we have developed a peptide phage display library screening method for novel transduction peptides able to facilitate tissue-specific internalization of marker protein complexes. Using this approach, we have identified transduction peptides that are able to facilitate internalization of large protein complexes into tumours, airway epithelia, synovial fibroblasts, cardiac tissue and HEK-293 (human embryonic kidney) cells in culture and/or in vivo.
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August 2007
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Conference Article|
July 20 2007
Protein transduction: identification, characterization and optimization
J. Tilstra;
J. Tilstra
1
*Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
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K.K. Rehman;
K.K. Rehman
1
†Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
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T. Hennon;
T. Hennon
†Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
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S.E. Plevy;
S.E. Plevy
*Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
‡Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
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P. Clemens;
P. Clemens
§Neurology Service, Department of Veterans Affairs Medical Center, Pittsburgh, PA 15240, U.S.A.
∥Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
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P.D. Robbins
P.D. Robbins
2
*Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
†Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, U.S.A.
2To whom correspondence should be addressed (email probb@pitt.edu).
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Publisher: Portland Press Ltd
Received:
May 18 2007
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2007 Biochemical Society
2007
Biochem Soc Trans (2007) 35 (4): 811–815.
Article history
Received:
May 18 2007
Citation
J. Tilstra, K.K. Rehman, T. Hennon, S.E. Plevy, P. Clemens, P.D. Robbins; Protein transduction: identification, characterization and optimization. Biochem Soc Trans 1 August 2007; 35 (4): 811–815. doi: https://doi.org/10.1042/BST0350811
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