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Cell-Penetrating Peptide Conjugates Of Peptide Nucleic Acids (Pna) As
Inhibitors Of Hiv-1 Tat-Dependent Trans-Activation In Cells. ...
Submitted by paperboy9x on April 29, 2008
Category: Science
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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@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...
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