Peptide nucleic acids conjugated to short basic peptides show improved pharmacokinetics and antisense activity in adipose tissue

Edward V. Wancewicz, Martin A. Maier, Andrew M. Siwkowski, Klaus Albertshofer, Theodore M. Winger, Andres Berdeja, Hans Gaus, Timothy A. Vickers, C. Frank Bennett, Brett P. Monia, Richard H. Griffey, Christopher J. Nulf, Jiaxin Hu, David R. Corey, Eric E. Swayze, Garth A. Kinberger

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

A peptide nucleic acid (PNA) targeting a splice junction of the murine PTEN primary transcript was covalently conjugated to various basic peptides. When systemically administered to healthy mice, the conjugates displayed sequence-specific alteration of PTEN mRNA splicing as well as inhibition of full length PTEN protein expression. Correlating activity with drug concentration in various tissues indicated strong tissue-dependence, with highest levels of activity observed in adipose tissue. While the presence of a peptide carrier was found to be crucial for efficient delivery to tissue, little difference was observed between the various peptides evaluated. A second PNA-conjugate targeting the murine insulin receptor primary transcript showed a similar activity profile, suggesting that short basic peptides can generally be used to effectively deliver peptide nucleic acids to adipose tissue.

Original languageEnglish (US)
Pages (from-to)3919-3926
Number of pages8
JournalJournal of Medicinal Chemistry
Volume53
Issue number10
DOIs
StatePublished - May 27 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Wancewicz, E. V., Maier, M. A., Siwkowski, A. M., Albertshofer, K., Winger, T. M., Berdeja, A., Gaus, H., Vickers, T. A., Bennett, C. F., Monia, B. P., Griffey, R. H., Nulf, C. J., Hu, J., Corey, D. R., Swayze, E. E., & Kinberger, G. A. (2010). Peptide nucleic acids conjugated to short basic peptides show improved pharmacokinetics and antisense activity in adipose tissue. Journal of Medicinal Chemistry, 53(10), 3919-3926. https://doi.org/10.1021/jm901489k