title: An anti-apoptotic peptide improves survival in lethal total body irradiation.
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 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.
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO 63110, USA. mcdunnj@wustl.edu
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: McDunn
authors.forename: Jared T
authors.initials: JT
authors.lastname: Muenzer
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dunne
authors.forename: Anthony
authors.initials: A
authors.lastname: Zhou
authors.forename: Kevin
authors.initials: K
authors.lastname: Yuan
authors.forename: Andrew
authors.initials: A
authors.lastname: Hoekzema
authors.forename: Carolyn
authors.initials: C
authors.lastname: Hilliard
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Chang
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Davis
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: McDonough
authors.forename: Clayton
authors.initials: C
authors.lastname: Hunt
authors.forename: Perry
authors.initials: P
authors.lastname: Grigsby
authors.forename: David
authors.initials: D
authors.lastname: Piwnica-Worms
authors.forename: Richard S
authors.initials: RS
authors.lastname: Hotchkiss
mesh_terms: 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
chemical_list: 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