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

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

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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 (5-10 μM) 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.

Original languageEnglish
Pages (from-to)657-662
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume382
Issue number4
DOIs
StatePublished - May 15 2009

Keywords

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

Fingerprint Dive into the research topics of 'An anti-apoptotic peptide improves survival in lethal total body irradiation'. Together they form a unique fingerprint.

Cite this