title: Q-VD-OPh, a broad spectrum caspase inhibitor with potent antiapoptotic properties.
abstract: In recent years, several inhibitors that prevent caspase activation and apoptosis have emerged. At high doses, however, these inhibitors can have nonspecific effects and/or become cytotoxic. In this study, we determined the effectiveness of broad spectrum caspase inhibitors to prevent apoptosis. A carboxy terminal phenoxy group conjugated to the amino acids valine and aspartate (Q-VD-OPh) potently inhibited apoptosis. Q-VD-OPh was significantly more effective in preventing apoptosis than the widely used inhibitors, ZVAD-fmk and Boc-D-fmk, and was also equally effective in preventing apoptosis mediated by the three major apoptotic pathways, caspase 9/3, caspase 8/10, and caspase 12. In addition to the increased effectiveness, Q-VD-OPh was not toxic to cells even at extremely high concentrations. Our data indicate that the specificity, effectiveness, and reduced toxicity of caspase inhibitors can be significantly enhanced using carboxyterminal o-phenoxy groups and may have important uses in vivo.
authors.affiliation: Department of Physiology and Biophysics, Wright State University School of Medicine, Dayton, Ohio 45435, USA.
authors.forename: T M
authors.initials: TM
authors.lastname: Caserta
authors.forename: A N
authors.initials: AN
authors.lastname: Smith
authors.forename: A D
authors.initials: AD
authors.lastname: Gultice
authors.forename: M A
authors.initials: MA
authors.lastname: Reedy
authors.forename: T L
authors.initials: TL
authors.lastname: Brown
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001593:Benzyl Compounds / Q000378:metabolism / Q000494:pharmacology; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D053938:DNA Fragmentation; D003609:Dactinomycin / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000378:metabolism / Q000494:pharmacology; D019169:Jurkat Cells; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D019284:Thapsigargin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D001593:Benzyl Compounds; C476029:Boc-D-FMK; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D006845:Hydrocarbons, Fluorinated; D019384:Nucleic Acid Synthesis Inhibitors; D011804:Quinolines; D016212:Transforming Growth Factor beta; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C468548:quinoline-val-asp(OMe)-CH2-OPH; D003609:Dactinomycin; D019284:Thapsigargin