A Targeted Peptide Nucleic Acid To Down-Regulate Mouse Microsomal Triglyceride Transfer Protein Expression in Hepatocytes
Autor: | Theo J.C. Van Berkel, Karen Sliedregt-Bol, Sabine M.W. van Rossenberg, Perry Prince, Erik A.L. Biessen, Jacques H. van Boom, Gijs A. van der Marel |
---|---|
Rok vydání: | 2003 |
Předmět: |
Male
Peptide Nucleic Acids Biomedical Engineering Down-Regulation Pharmaceutical Science Bioengineering Peptide DNA Antisense Protein Structure Secondary Microsomal triglyceride transfer protein Mice chemistry.chemical_compound Drug Delivery Systems Transcription (biology) Animals RNA Messenger Pharmacology chemistry.chemical_classification Messenger RNA Peptide nucleic acid biology musculoskeletal neural and ocular physiology Organic Chemistry Biological Transport Prodrug Molecular biology Mice Inbred C57BL chemistry Biochemistry Drug Design biological sciences Hepatocytes Microsomes Liver cardiovascular system Nucleic acid biology.protein Asialoglycoprotein receptor Carrier Proteins tissues Biotechnology |
Zdroj: | Bioconjugate Chemistry. 14:1077-1082 |
ISSN: | 1520-4812 1043-1802 |
Popis: | Peptide nucleic acids (PNA's) have shown to hold potential as antisense drugs. In this study we have designed PNA drugs for the microsomal triglyceride transfer protein (MTP), which is known to play a critical role in the assembly of atherogenic lipoproteins, and have converted the most potent drug into a liver-targeted prodrug. First, we have synthesized three PNA sequences targeting domains on the mouse MTP mRNA, which were not involved in intrastrand base-pairing interactions as jugded from its secondary structure. Only one of the PNA's, PNA569, showed dose-dependent inhibition of MTP expression in a cell-free system for coupled transcription/translation of MTP. Second, to improve the cellular uptake of this PNA drug, we have conjugated PNA569 to a high affinity ligand for the asialoglycoprotein receptor, K(GalNAc)(2). As compared to the parent PNA, the prodrug PNA-K(GalNAc)(2) was found to display to a markedly improved capacity to inhibit MTP mRNA expression in parenchymal liver cells. A glycoconjugated nonsense control appeared to be ineffective. In conclusion, the design of a targeted PNA is described to reduce MTP expression in parenchymal liver cells by 70%. The presented approach for targeted tissue-specific down-regulation of genes by PNA's may be valid for other genes as well. |
Databáze: | OpenAIRE |
Externí odkaz: |