A Targeted Peptide Nucleic Acid To Down-Regulate Mouse Microsomal Triglyceride Transfer Protein Expression in Hepatocytes

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• 作者：Sabine M. W. van Rossenberg ; Karen M. Sliedregt-Bol ; Perry Prince ; Theo J. C. van Berkel ; Jacques H. van Boom ; Gijs A. van der Marel ; and Erik A. L. Biessen
• 刊名：Bioconjugate Chemistry
• 出版年：2003
• 出版时间：November 2003
• 年：2003
• 卷：14
• 期：6
• 页码：1077 - 1082
• 全文大小：74K
• 年卷期：v.14,no.6(November 2003)
• ISSN：1520-4812

文摘

Peptide nucleic acids (PNA's) have shown to hold potential as antisense drugs. In this study we havedesigned PNA drugs for the microsomal triglyceride transfer protein (MTP), which is known to playa critical role in the assembly of atherogenic lipoproteins, and have converted the most potent druginto a liver-targeted prodrug. First, we have synthesized three PNA sequences targeting domains onthe mouse MTP mRNA, which were not involved in intrastrand base-pairing interactions as jugdedfrom its secondary structure. Only one of the PNA's, PNA569, showed dose-dependent inhibition ofMTP expression in a cell-free system for coupled transcription/translation of MTP. Second, to improvethe cellular uptake of this PNA drug, we have conjugated PNA569 to a high affinity ligand for theasialoglycoprotein 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 expressionin 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 by70%. The presented approach for targeted tissue-specific down-regulation of genes by PNA's may bevalid for other genes as well.