An anti-apoptotic peptide improves survival in lethal total body irradiation.
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.
McDunn
Jonathan E
JE
Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO 63110, USA. mcdunnj@wustl.edu
Muenzer
Jared T
JT
Dunne
Benjamin
B
Zhou
Anthony
A
Yuan
Kevin
K
Hoekzema
Andrew
A
Hilliard
Carolyn
C
Chang
Katherine C
KC
Davis
Christopher G
CG
McDonough
Jacquelyn
J
Hunt
Clayton
C
Grigsby
Perry
P
Piwnica-Worms
David
D
Hotchkiss
Richard S
RS
D000595:Amino Acid Sequence; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D014916:Whole-Body Irradiation; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
D000952:Antigens, Polyomavirus Transforming; C540573:NLS-BH4 protein; D019913:Nuclear Localization Signals; D010455:Peptides; C540574:TAT-BH4 peptide; D051020:bcl-X Protein; D054322:tat Gene Products, Human Immunodeficiency Virus