The cellular uptake of PMOs (phosphorodiamidate morpholino oligomers) can be enhanced by their conjugation to arginine-rich CPPs (cell-penetrating peptides). Here, we discuss our recent findings regarding (R-Ahx-R)4AhxB (Ahx is 6-aminohexanoic acid and B is β-alanine) CPP–PMO conjugates in DMD (Duchenne muscular dystrophy) and murine coronavirus research. An (R-Ahx-R)4AhxB–PMO conjugate was the most effective compound in inducing the correction of mutant dystrophin transcripts in myoblasts derived from a canine model of DMD. Similarly, normal levels of dystrophin expression were restored in the diaphragms of mdx mice, with treatment starting at the neonatal stage, and protein was still detecTable 22 weeks after the last dose of an (R-Ahx-R)4AhxB–PMO conjugate. Effects of length, linkage and carbohydrate modification of this CPP on the delivery of a PMO were investigated in a coronavirus mouse model. An (R-Ahx-R)4AhxB–PMO conjugate effectively inhibited viral replication, in comparison with other peptides conjugated to the same PMO. Shortening the CPP length, modifying it with a mannosylated serine moiety or replacing it with the R9F2 CPP significantly decreased the efficacy of the resulting PPMO (CPP–PMO conjugate). We attribute the success of this CPP to its stability in serum and its capacity to transport PMO to RNA targets in a manner superior to that of poly-arginine CPPs.
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August 2007
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Conference Article|
July 20 2007
Cell-penetrating peptide–morpholino conjugates alter pre-mRNA splicing of DMD (Duchenne muscular dystrophy) and inhibit murine coronavirus replication in vivo
H.M. Moulton;
H.M. Moulton
1
*AVI BioPharma Inc., 4575 SW Research Way, Corvallis, OR 97333, U.S.A.
1To whom correspondence should be addressed (email moulton@avibio.com).
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S. Fletcher;
S. Fletcher
†University of Western Australia, Perth, Western Australia, 6009, Australia
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B.W. Neuman;
B.W. Neuman
‡The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, U.S.A.
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G. McClorey;
G. McClorey
†University of Western Australia, Perth, Western Australia, 6009, Australia
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D.A. Stein;
D.A. Stein
*AVI BioPharma Inc., 4575 SW Research Way, Corvallis, OR 97333, U.S.A.
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S. Abes;
S. Abes
§UMR 5235 CNRS, Université Montpellier 2, Place Eugène Bataillon, 34095 Montpellier cedex 5, France
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S.D. Wilton;
S.D. Wilton
†University of Western Australia, Perth, Western Australia, 6009, Australia
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M.J. Buchmeier;
M.J. Buchmeier
‡The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, U.S.A.
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B. Lebleu;
B. Lebleu
§UMR 5235 CNRS, Université Montpellier 2, Place Eugène Bataillon, 34095 Montpellier cedex 5, France
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P.L. Iversen
P.L. Iversen
*AVI BioPharma Inc., 4575 SW Research Way, Corvallis, OR 97333, U.S.A.
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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): 826–828.
Article history
Received:
May 18 2007
Citation
H.M. Moulton, S. Fletcher, B.W. Neuman, G. McClorey, D.A. Stein, S. Abes, S.D. Wilton, M.J. Buchmeier, B. Lebleu, P.L. Iversen; Cell-penetrating peptide–morpholino conjugates alter pre-mRNA splicing of DMD (Duchenne muscular dystrophy) and inhibit murine coronavirus replication in vivo. Biochem Soc Trans 1 August 2007; 35 (4): 826–828. doi: https://doi.org/10.1042/BST0350826
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