About this item:

92 Views | 79 Downloads

Author Notes:

Correspondence: noxdoc@mac.com

We gratefully acknowledge the generous gifts of Nox1 and Nox4 stably transfected cell lines from Dr. Ralf Brandes (Goethe University, Frankfurt), antibody to p47phox from Dr. Jamal El-Benna (INSERM, Paris), and antibodies to p47phox and p67phox from Dr. Mark Quinn (Montana State University, Montana).

The authors declare that they have no competing interests in this work.

Subjects:

Research Funding:

The work was supported by NIH R03 MH083234 to SMES and NIH R01 CA084138 and R01CA084138-08S1 to JDL.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • RESPIRATORY BURST OXIDASE
  • SH3 DOMAIN INTERACTIONS
  • RAT KUPFFER CELLS
  • OXIDATIVE STRESS
  • SELENOORGANIC COMPOUND
  • NAD(P)H OXIDASE
  • REACTIVE OXYGEN
  • NITRIC-OXIDE
  • NOX ENZYMES
  • DIABETIC-NEPHROPATHY

Ebselen and Congeners Inhibit NADPH Oxidase 2-Dependent Superoxide Generation by Interrupting the Binding of Regulatory Subunits

Show all authors Show less authors

Tools:

Journal Title:

Cell Chemistry Biology

Volume:

Volume 19, Number 6

Publisher:

, Pages 752-763

Type of Work:

Article | Post-print: After Peer Review

Abstract:

NADPH oxidases (Nox) are a primary source of reactive oxygen species (ROS), which function in normal physiology and, when overproduced, in pathophysiology. Recent studies using mice deficient in Nox2 identify this isoform as a novel target against Nox2-implicated inflammatory diseases. Nox2 activation depends on the binding of the proline-rich domain of its heterodimeric partner p22phox to p47phox. A high-throughput screen that monitored this interaction via fluorescence polarization identified ebselen and several of its analogs as inhibitors. Medicinal chemistry was performed to explore structure-activity relationships and to optimize potency. Ebselen and analogs potently inhibited Nox1 and Nox2 activity but were less effective against other isoforms. Ebselen also blocked translocation of p47phox to neutrophil membranes. Thus, ebselen and its analogs represent a class of compounds that inhibit ROS generation by interrupting the assembly of Nox2-activating regulatory subunits.

Copyright information:

© 2012 Elsevier Ltd All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Creative Commons License

Export to EndNote