Structure−Activity Relationship Study on a Simple Cationic Peptide Motif for Cellular Delivery of Antisense Peptide Nucleic Acid
| Autor: | Kenji C Nishihara, Klaus Albertshofer, Brett P. Monia, Eric E. Swayze, Martin Maier, Leila Malik, Andrew M. Siwkowski, C. Frank Bennett, Anne B. Eldrup, Edward Wancewicz, Garth A. Kinberger, Richard S. Geary, Christine Esau, Richard H. Griffey, Muthiah Manoharan, Tanya Watanabe |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Peptide Nucleic Acids Biodistribution Cell Survival Peptide Arginine Mice Structure-Activity Relationship chemistry.chemical_compound Cations Cell Line Tumor Drug Discovery Animals Structure–activity relationship Tissue Distribution chemistry.chemical_classification Drug Carriers Mice Inbred BALB C Oligopeptide Peptide nucleic acid Lysine chemistry Biochemistry RNA splicing Nucleic acid Molecular Medicine Hydrophobic and Hydrophilic Interactions Oligopeptides Conjugate |
| Zdroj: | Journal of Medicinal Chemistry. 48:6741-6749 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm050490b |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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