Q-VD-OPh, a broad spectrum caspase inhibitor with potent antiapoptotic properties.
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.
Caserta
T M
TM
Department of Physiology and Biophysics, Wright State University School of Medicine, Dayton, Ohio 45435, USA.
Smith
A N
AN
Gultice
A D
AD
Reedy
M A
MA
Brown
T L
TL
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
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