title: Arginine-rich cell penetrating peptides: design, structure-activity, and applications to alter pre-mRNA splicing by steric-block oligonucleotides.
abstract: 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, Arg9, Lys8, 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.
authors.affiliation: UMR 5235 CNRS, Université Montpellier 2, Place Eugene Bataillon, 34095 Montpellier cedex 5, France.
authors.forename: R
authors.initials: R
authors.lastname: Abes
authors.forename: A
authors.initials: A
authors.lastname: Arzumanov
authors.forename: H
authors.initials: H
authors.lastname: Moulton
authors.forename: S
authors.initials: S
authors.lastname: Abes
authors.forename: G
authors.initials: G
authors.lastname: Ivanova
authors.forename: M J
authors.initials: MJ
authors.lastname: Gait
authors.forename: P
authors.initials: P
authors.lastname: Iversen
authors.forename: B
authors.initials: B
authors.lastname: Lebleu
mesh_terms: D000818:Animals; D001120:Arginine / Q000737:chemistry*; D002462:Cell Membrane / Q000378:metabolism; D002463:Cell Membrane Permeability; D006801:Humans; D009841:Oligonucleotides / Q000737:chemistry*; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism*; D012322:RNA Precursors / Q000378:metabolism*; D012326:RNA Splicing; D013329:Structure-Activity Relationship
chemical_list: D009841:Oligonucleotides; D010455:Peptides; D012322:RNA Precursors; D001120:Arginine