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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 (5-10 microM) 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.

Citation

Jonathan E McDunn, Jared T Muenzer, Benjamin Dunne, Anthony Zhou, Kevin Yuan, Andrew Hoekzema, Carolyn Hilliard, Katherine C Chang, Christopher G Davis, Jacquelyn McDonough, Clayton Hunt, Perry Grigsby, David Piwnica-Worms, Richard S Hotchkiss. An anti-apoptotic peptide improves survival in lethal total body irradiation. Biochemical and biophysical research communications. 2009 May 15;382(4):657-62

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PMID: 19303399

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