Q-VD-OPh, a broad spectrum caspase inhibitor with potent antiapoptotic properties

T M Caserta; A N Smith; A D Gultice; M A Reedy; T L Brown

doi:10.1023/a:1024116916932

Q-VD-OPh, a broad spectrum caspase inhibitor with potent antiapoptotic properties

Apoptosis. 2003 Aug;8(4):345-52. doi: 10.1023/a:1024116916932.

Authors

T M Caserta¹, A N Smith, A D Gultice, M A Reedy, T L Brown

Affiliation

¹ Department of Physiology and Biophysics, Wright State University School of Medicine, Dayton, Ohio 45435, USA.

PMID: 12815277
DOI: 10.1023/a:1024116916932

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Chloromethyl Ketones / chemistry
Amino Acid Chloromethyl Ketones / metabolism
Amino Acid Chloromethyl Ketones / pharmacology*
Animals
Apoptosis / drug effects*
Apoptosis / physiology
Benzyl Compounds / metabolism
Benzyl Compounds / pharmacology
Caspase Inhibitors*
Cysteine Proteinase Inhibitors / metabolism
Cysteine Proteinase Inhibitors / pharmacology*
DNA Fragmentation
Dactinomycin / metabolism
Humans
Hydrocarbons, Fluorinated / metabolism
Hydrocarbons, Fluorinated / pharmacology
Jurkat Cells
Mice
Nucleic Acid Synthesis Inhibitors / metabolism
Quinolines / chemistry
Quinolines / metabolism
Quinolines / pharmacology*
Rats
Thapsigargin / metabolism
Transforming Growth Factor beta / metabolism

Substances

Amino Acid Chloromethyl Ketones
Benzyl Compounds
Boc-D-FMK
Caspase Inhibitors
Cysteine Proteinase Inhibitors
Hydrocarbons, Fluorinated
Nucleic Acid Synthesis Inhibitors
Quinolines
Transforming Growth Factor beta
benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
quinoline-val-asp(OMe)-CH2-OPH
Dactinomycin
Thapsigargin