期刊
JOURNAL OF PEPTIDE SCIENCE
卷 14, 期 4, 页码 455-460出版社
WILEY
DOI: 10.1002/psc.979
关键词
cell penetrating peptides; steric-block oligonucleotides; splicing correction; delivery
资金
- Medical Research Council [MC_U105178803] Funding Source: Medline
- MRC [MC_U105178803] Funding Source: UKRI
- Medical Research Council [MC_U105178803] Funding Source: researchfish
Rerouting the splicing machinery with steric-block oligonucleotides (ON) might lead to new therapeutic strategies in the treatment of diseases such as beta-thalassemia, Duchenne muscular dystrophy, or cancers. Interfering with splicing requires the sequence-specific and stable hybridization of RNase H-incompetent ON as peptide nucleic acids (PNA) or phosphorodiamidate morpholino oligomers (PMO). Unfortunately, these uncharged DNA mimics are poorly taken up by most cell types and conventional delivery strategies that rely on electrostatic interaction do not apply. Likewise, conjugation to cell penetrating peptides (CPPs) as Tat, Arg(9), Lys(8), or Pen leads to poor splicing correction efficiency at low concentration essentially because PNA- and PMO-CPP conjugates remain entrapped within endocytotic vesicles. Recently, we have designed an arginine-rich peptide (R-Ahx-R)(4) (with Ahx for aminohexanoic acid) and an arginine-tailed Penetratin derivative which allow sequence-specific and efficient splicing correction at low concentration in the absence of endosomolytic agents. Both CPPs are undergoing structure-activity relationship studies for further optimization as steric-block ON delivery vectors. Copyright (c) 2008 European Peptide Society and John Wiley & Sons. Ltd.
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