title: Structure-activity relationship study on a simple cationic peptide motif for cellular delivery of antisense peptide nucleic acid.
abstract: Improving cellular uptake and biodistribution remains one of the major obstacles for a successful and broad application of peptide nucleic acids (PNAs) as antisense therapeutics. Recently, we reported the identification and functional characterization of an antisense PNA, which redirects splicing of murine CD40 pre-mRNA. In this context, it was discovered that a simple octa(l-lysine) peptide covalently linked to the PNA is capable of promoting free uptake of the conjugate into BCL1 cells as well as primary murine macrophages. On the basis of this peptide motif, the present study aimed at identifying the structural features, which define effective peptide carriers for cellular delivery of PNA. While the structure-activity relationship study revealed some clear correlations, only a few modifications actually led to an overall improvement as compared to the parent octa(l-lysine) conjugate. In a preliminary PK/tissue distribution study in healthy mice, the parent conjugate exhibited relatively broad tissue distribution and only modest elimination via excretion within the time frame of the study.
authors.affiliation: Department of Medicinal Chemistry, Isis Pharmaceuticals, Inc., 1891 Rutherford Road, Carlsbad, CA 92008, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Albertshofer
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Siwkowski
authors.forename: Edward V
authors.initials: EV
authors.lastname: Wancewicz
authors.forename: Christine C
authors.initials: CC
authors.lastname: Esau
authors.forename: Tanya
authors.initials: T
authors.lastname: Watanabe
authors.forename: Kenji C
authors.initials: KC
authors.lastname: Nishihara
authors.forename: Garth A
authors.initials: GA
authors.lastname: Kinberger
authors.forename: Leila
authors.initials: L
authors.lastname: Malik
authors.forename: Anne B
authors.initials: AB
authors.lastname: Eldrup
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
authors.forename: Richard S
authors.initials: RS
authors.lastname: Geary
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.forename: Eric E
authors.initials: EE
authors.lastname: Swayze
authors.forename: Richard H
authors.initials: RH
authors.lastname: Griffey
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.forename: Martin A
authors.initials: MA
authors.lastname: Maier
mesh_terms: D000818:Animals; D001120:Arginine / Q000737:chemistry*; D002412:Cations; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D008239:Lysine / Q000737:chemistry*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D020135:Peptide Nucleic Acids / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D002412:Cations; D004337:Drug Carriers; D009842:Oligopeptides; D020135:Peptide Nucleic Acids; D001120:Arginine; D008239:Lysine