An anti-apoptotic peptide improves survival in lethal total body irradiation

作者：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; Grig**y Perry; Piwnica Worms David; Hotchkiss Richard S

来源：Biochemical and Biophysical Research Communications, 2009, 382(4): 657-662.

DOI：10.1016/j.bbrc.2009.03.080

• Cell penetrating motif
• NLS
• TAT
• Bcl-2
• BH4
• Cell death
• Apoptosis
• Necrosis
• Total body irradiation

Cell penetrating peptides (CPPs) have been used to deliver the anti-apoptotic Bcl-xL-derived BH4 peptide to prevent injury-induced 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 mu M) 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.

• 出版日期2009-5-15