Skip Navigation

Nucleic Acids Research 2005 33(21):6837-6849; doi:10.1093/nar/gki991
This Article
Right arrow Full Text Freely available
Right arrow Print PDF (633K) Freely available
Right arrow Screen PDF (643K) Freely available
Right arrow Supplementary Material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (61)
Right arrow Commercial Re-use Guidelines
for Open Access NAR Content
Google Scholar
Right arrow Articles by Turner, J. J.
Right arrow Articles by Gait, M. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Turner, J. J.
Right arrow Articles by Gait, M. J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published online 30 November 2005

© The Author 2005. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions{at}oxfordjournals.org

Article

Cell-penetrating peptide conjugates of peptide nucleic acids (PNA) as inhibitors of HIV-1 Tat-dependent trans-activation in cells

John J. Turner, Gabriela D. Ivanova, Birgit Verbeure, Donna Williams, Andrey A. Arzumanov, Saïd Abes1, Bernard Lebleu1 and Michael J. Gait*

Laboratory of Molecular Biology, Medical Research Council Hills Road, Cambridge CB2 2QH, UK 1UMR 5124 CNRS, CC 086, Université Montpellier 2 Place Eugène Bataillon, 34095 Montpellier, France

*To whom correspondence should be addressed. Tel: +44 1223 248011; Fax: +44 1223 402070; Email: mgait{at}mrc-lmb.cam.ac.uk

Received October 6, 2005. Revised November 14, 2005. Accepted November 14, 2005.

The trans-activation response (TAR) RNA stem–loop that occurs at the 5' end of HIV RNA transcripts is an important antiviral target and is the site of interaction of the HIV-1 Tat protein together with host cellular factors. Oligonucleotides and their analogues targeted to TAR are potential antiviral candidates. We have investigated a range of cell penetrating peptide (CPP) conjugates of a 16mer peptide nucleic acid (PNA) analogue targeted to the apical stem–loop of TAR and show that disulfide-linked PNA conjugates of two types of CPP (Transportan or a novel chimeric peptide R6-Penetratin) exhibit dose-dependent inhibition of Tat-dependent trans-activation in a HeLa cell assay when incubated for 24 h. Activity is reached within 6 h if the lysosomotropic reagent chloroquine is co-administered. Fluorescein-labelled stably-linked conjugates of Tat, Transportan or Transportan TP10 with PNA were inactive when delivered alone, but attained trans-activation inhibition in the presence of chloroquine. Confocal microscopy showed that such fluorescently labelled CPP–PNA conjugates were sequestered in endosomal or membrane-bound compartments of HeLa cells, which varied in appearance depending on the CPP type. Co-administration of chloroquine was seen in some cases to release fluorescence from such compartments into the nucleus, but with different patterns depending on the CPP. The results show that CPP–PNA conjugates of different types can inhibit Tat-dependent trans-activation in HeLa cells and have potential for development as antiviral agents. Endosomal or membrane release is a major factor limiting nuclear delivery and trans-activation inhibition.

Present address: Birgit Verbeure, Centre for Intellectual Property Rights, Catholic University of Leuven, Minderbroederstraat 5, B-3000 Leuven, Belgium


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Nucleic Acids ResHome page
G. D. Ivanova, A. Arzumanov, R. Abes, H. Yin, M. J. A. Wood, B. Lebleu, and M. J. Gait
Improved cell-penetrating peptide-PNA conjugates for splicing redirection in HeLa cells and exon skipping in mdx mouse muscle
Nucleic Acids Res., November 1, 2008; 36(20): 6418 - 6428.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
R. Juliano, Md. R. Alam, V. Dixit, and H. Kang
Mechanisms and strategies for effective delivery of antisense and siRNA oligonucleotides
Nucleic Acids Res., July 1, 2008; 36(12): 4158 - 4171.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
M. R. Alam, V. Dixit, H. Kang, Z.-B. Li, X. Chen, J. Trejo, M. Fisher, and R. L. Juliano
Intracellular delivery of an anionic antisense oligonucleotide via receptor-mediated endocytosis
Nucleic Acids Res., May 1, 2008; 36(8): 2764 - 2776.
[Abstract] [Full Text] [PDF]

Home page
 RNAHome page
M. M. Fabani and M. J. Gait
miR-122 targeting with LNA/2'-O-methyl oligonucleotide mixmers, peptide nucleic acids (PNA), and PNA-peptide conjugates
RNA, February 1, 2008; 14(2): 336 - 346.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
K. Gogoi, M. V. Mane, S. S. Kunte, and V. A. Kumar
A versatile method for the preparation of conjugates of peptides with DNA/PNA/analog by employing chemo-selective click reaction in water
Nucleic Acids Res., December 18, 2007; 35(21): e139 - e139.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
S. Abes, J. J. Turner, G. D. Ivanova, D. Owen, D. Williams, A. Arzumanov, P. Clair, M. J. Gait, and B. Lebleu
Efficient splicing correction by PNA conjugation to an R6-Penetratin delivery peptide
Nucleic Acids Res., July 26, 2007; 35(13): 4495 - 4502.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
M. C. Morris, E. Gros, G. Aldrian-Herrada, M. Choob, J. Archdeacon, F. Heitz, and G. Divita
A non-covalent peptide-based carrier for in vivo delivery of DNA mimics
Nucleic Acids Res., April 1, 2007; 35(7): e49 - e49.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
S. Veldhoen, S. D. Laufer, A. Trampe, and T. Restle
Cellular delivery of small interfering RNA by a non-covalently attached cell-penetrating peptide: quantitative analysis of uptake and biological effect
Nucleic Acids Res., December 2, 2006; 34(22): 6561 - 6573.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
K. Pachulska-Wieczorek, K. J. Purzycka, and R. W. Adamiak
New, extended hairpin form of the TAR-2 RNA domain points to the structural polymorphism at the 5' end of the HIV-2 leader RNA
Nucleic Acids Res., May 31, 2006; 34(10): 2984 - 2997.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
V. A. Efimov, K. R. Birikh, D. B. Staroverov, S. A. Lukyanov, M. B. Tereshina, A. G. Zaraisky, and O. G. Chakhmakhcheva
Hydroxyproline-based DNA mimics provide an efficient gene silencing in vitro and in vivo.
Nucleic Acids Res., January 1, 2006; 34(8): 2247 - 2257.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.