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Nucleic Acids Research Advance Access originally published online on June 21, 2007
Nucleic Acids Research 2007 35(13):4495-4502; doi:10.1093/nar/gkm418
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Nucleic Acids Research, 2007, Vol. 35, No. 13 4495-4502
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

Efficient splicing correction by PNA conjugation to an R6-Penetratin delivery peptide

Saïd Abes1, John J. Turner2, Gabriela D. Ivanova2, David Owen2, Donna Williams2, Andrey Arzumanov2, Philippe Clair, Michael J. Gait2 and Bernard Lebleu1,*

1UMR 5235 CNRS, Université Montpellier 2, Place Eugene Bataillon, 34095 Montpellier cedex 5, France and 2Medical Research Council, Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH UK

*To whom correspondence should be addressed. Tel: +33 467 14 92 03; Fax: +33 467 14 92 01; Email: bernard.lebleu{at}univ-montp2.fr Correspondence may also be addressed to Michael J. Gait. Tel: +44 1223 248011; Fax: +441223 402070; Email: mgait{at}mrc-lmb.cam.ac.uk

Received January 31, 2007. Revised April 20, 2007. Accepted May 7, 2007.

Sequence-specific interference with the nuclear pre-mRNA splicing machinery has received increased attention as an analytical tool and for development of therapeutics. It requires sequence-specific and high affinity binding of RNaseH-incompetent DNA mimics to pre-mRNA. Peptide nucleic acids (PNA) or phosphoramidate morpholino oligonucleotides (PMO) are particularly suited as steric block oligonucleotides in this respect. However, splicing correction by PNA or PMO conjugated to cell penetrating peptides (CPP), such as Tat or Penetratin, has required high concentrations (5–10 µM) of such conjugates, unless an endosomolytic agent was added to increase escape from endocytic vesicles. We have focused on the modification of existing CPPs to search for peptides able to deliver more efficiently splice correcting PNA or PMO to the nucleus in the absence of endosomolytic agents. We describe here R6-Penetratin (in which arginine-residues were added to the N-terminus of Penetratin) as the most active of all CPPs tested so far in a splicing correction assay in which masking of a cryptic splice site allows expression of a luciferase reporter gene. Efficient and sequence-specific correction occurs at 1 µM concentration of the R6Pen–PNA705 conjugate as monitored by luciferase luminescence and by RT-PCR. Some aspects of the R6Pen–PNA705 structure–function relationship have also been evaluated.


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