1. An anti-apoptotic peptide improves survival in lethal total body irradiation
- Author
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McDunn, Jonathan E., Muenzer, Jared T., Dunne, Benjamin, Zhou, Anthony, Yuan, Kevin, Hoekzema, Andrew, Hilliard, Carolyn, Chang, Katherine C., Davis, Christopher G., McDonough, Jacquelyn, Hunt, Clayton, Grigsby, Perry, Piwnica-Worms, David, and Hotchkiss, Richard S.
- Subjects
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PEPTIDES , *PHYSIOLOGICAL effects of radiation , *NUCLEOTIDE sequence , *NECROSIS , *LYMPHOCYTES ,APOPTOSIS prevention - Abstract
Abstract: Cell penetrating peptides (CPPs) have been used to deliver the anti-apoptotic Bcl-xL-derived BH4 peptide to prevent injury-induced apoptosis both in vitro and in vivo. Here we demonstrate that the nuclear localization sequence (NLS) from the SV40 large T antigen has favorable properties for BH4 domain delivery to lymphocytes compared to sequences based on the HIV-1 TAT sequence. While both TAT-BH4 and NLS-BH4 protected primary human mononuclear cells from radiation-induced apoptotic cell death, TAT-BH4 caused persistent membrane damage and even cell death at the highest concentrations tested (5–10μM) and correlated with in vivo toxicity as intravenous administration of TAT-BH4 caused rapid death. The NLS-BH4 peptide has significantly attenuated toxicity compared to TAT-BH4 and we established a dosing regimen of NLS-BH4 that conferred a significant survival advantage in a post-exposure treatment model of LD90 total body irradiation. [Copyright &y& Elsevier]
- Published
- 2009
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