title: Evaluation of basic amphipathic peptides for cellular delivery of antisense peptide nucleic acids.
abstract: Cellular permeation peptides have been used successfully for the delivery of a variety of cargoes across cellular membranes, including large hydrophilic biomolecules such as proteins, oligonucleotides, or plasmid DNA. For the present work, a series of short amphipathic peptides was designed to elucidate the structural requirements for efficient and nontoxic delivery of peptide nucleic acids (PNAs). On the basis of an idealized alpha-helical structure, the helical parameters were modulated systematically to yield peptides within a certain range of hydrophobicity and amphipathicity. The corresponding PNA conjugates were synthesized and characterized in terms of secondary structure, enzymatic stability, and antisense activity. The study revealed correlations between the physicochemical and biophysical properties of the conjugates and their biological activity and led to the development of potent peptide vectors for the cellular delivery of antisense PNAs. Two representative compounds were radiolabeled and evaluated for their biodistribution in healthy mice.
authors.affiliation: Department of Medicinal Chemistry, Isis Pharmaceuticals Inc., 1891 Rutherford Road, Carlsbad, CA 92008, USA. mmaier@isisph.com
authors.forename: Martin A
authors.initials: MA
authors.lastname: Maier
authors.forename: Christine C
authors.initials: CC
authors.lastname: Esau
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Siwkowski
authors.forename: Edward V
authors.initials: EV
authors.lastname: Wancewicz
authors.forename: Klaus
authors.initials: K
authors.lastname: Albertshofer
authors.forename: Garth A
authors.initials: GA
authors.lastname: Kinberger
authors.forename: Neena S
authors.initials: NS
authors.lastname: Kadaba
authors.forename: Tanya
authors.initials: T
authors.lastname: Watanabe
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.forename: Richard H
authors.initials: RH
authors.lastname: Griffey
authors.forename: Eric E
authors.initials: EE
authors.lastname: Swayze
mesh_terms: D000818:Animals; D016375:Antisense Elements (Genetics) / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D015195:Drug Design; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020135:Peptide Nucleic Acids / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D013501:Surface-Active Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*
chemical_list: D016375:Antisense Elements (Genetics); D004337:Drug Carriers; D020135:Peptide Nucleic Acids; D010455:Peptides; D013501:Surface-Active Agents