Evaluation of Basic Amphipathic Peptides for Cellular Delivery of Antisense Peptide Nucleic Acids

• Published in: Journal of medicinal chemistry 2006-04, Vol.49 (8), p.2534-2542
• Main Authors: Maier, Martin A., Esau, Christine C., Siwkowski, Andrew M., Wancewicz, Edward V., Albertshofer, Klaus, Kinberger, Garth A., Kadaba, Neena S., Watanabe, Tanya, Manoharan, Muthiah, Bennett, C. Frank, Griffey, Richard H., Swayze, Eric E.
• Format: Article
• Language: English
• Subjects: Animals; Antisense Elements (Genetics) - administration & dosage; Antisense Elements (Genetics) - chemical synthesis; Antisense Elements (Genetics) - pharmacokinetics; Biological and medical sciences; Cell Line; Cell Membrane Permeability - drug effects; Cell Survival - drug effects; Drug Carriers - administration & dosage; Drug Carriers - chemical synthesis; Drug Carriers - pharmacokinetics; Drug Design; Male; Medical sciences; Mice; Mice, Inbred BALB C; Miscellaneous; Peptide Nucleic Acids - administration & dosage; Peptide Nucleic Acids - chemical synthesis; Peptide Nucleic Acids - pharmacokinetics; Peptides - administration & dosage; Peptides - chemical synthesis; Peptides - pharmacokinetics; Pharmacology. Drug treatments; Protein Structure, Secondary; Structure-Activity Relationship; Surface-Active Agents - administration & dosage; Surface-Active Agents - chemical synthesis; Surface-Active Agents - pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm051275y

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 α-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.