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

doi:10.1021/jm901489k

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 journal › Article › peer-review

26 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 language	English (US)
Pages (from-to)	3919-3926
Number of pages	8
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	10
DOIs	https://doi.org/10.1021/jm901489k
State	Published - May 27 2010

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/jm901489k

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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

Wancewicz, EV, Maier, MA, Siwkowski, AM, Albertshofer, K, Winger, TM, Berdeja, A, Gaus, H, Vickers, TA, Bennett, CF, Monia, BP, Griffey, RH, Nulf, CJ, Hu, J, Corey, DR, Swayze, EE & Kinberger, GA 2010, 'Peptide nucleic acids conjugated to short basic peptides show improved pharmacokinetics and antisense activity in adipose tissue', Journal of Medicinal Chemistry, vol. 53, no. 10, pp. 3919-3926. https://doi.org/10.1021/jm901489k

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

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.",

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

year = "2010",

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doi = "10.1021/jm901489k",

language = "English (US)",

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T1 - Peptide nucleic acids conjugated to short basic peptides show improved pharmacokinetics and antisense activity in adipose tissue

AU - Wancewicz, Edward V.

AU - Maier, Martin A.

AU - Siwkowski, Andrew M.

AU - Albertshofer, Klaus

AU - Winger, Theodore M.

AU - Berdeja, Andres

AU - Gaus, Hans

AU - Vickers, Timothy A.

AU - Bennett, C. Frank

AU - Monia, Brett P.

AU - Griffey, Richard H.

AU - Nulf, Christopher J.

AU - Hu, Jiaxin

AU - Corey, David R.

AU - Swayze, Eric E.

AU - Kinberger, Garth A.

PY - 2010/5/27

Y1 - 2010/5/27

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AB - 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.

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

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