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

• Type of Material: Article
• Authors: Susan Smith, Emory University; Jaeki Min, Emory University; Thota Ganesh, Emory University; Becky Diebold, Emory University; Tsukasa Kawahara, Emory University; Yerun Zhu, Emory University; James McCoy, Emory University; Aiming Sun, Emory University; James Snyder, Emory University; Haian Fu, Emory University; Yuhong Du, Emory University; Iestyn Lewis, Emory University; John Lambeth, Emory University
• Language: English
• Date: 2012-06-22
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Elsevier Ltd All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.chembiol.2012.04.015
• Title of Journal or Parent Work: Cell Chemistry Biology
• ISSN: 1074-5521
• Volume: 19
• Issue: 6
• Start Page: 752
• End Page: 763
• Grant/Funding Information: The work was supported by NIH R03 MH083234 to SMES and NIH R01 CA084138 and R01CA084138-08S1 to JDL.
• Keywords: DIABETIC-NEPHROPATHY; Life Sciences & Biomedicine; NAD(P)H OXIDASE; Science & Technology; RESPIRATORY BURST OXIDASE; Biochemistry & Molecular Biology; OXIDATIVE STRESS; REACTIVE OXYGEN; SELENOORGANIC COMPOUND; SH3 DOMAIN INTERACTIONS; RAT KUPFFER CELLS; NOX ENZYMES; NITRIC-OXIDE
• Research Categories: Health Sciences, Pathology; Health Sciences, Pharmacology; Chemistry, General

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.