Ebselen and congeners inhibit NADPH oxidase 2-dependent superoxide generation by interrupting the binding of regulatory subunits.
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.
Department of Pathology, Emory School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
Susan M E
SM
Smith
Jaeki
J
Min
Thota
T
Ganesh
Becky
B
Diebold
Tsukasa
T
Kawahara
Yerun
Y
Zhu
James
J
McCoy
Aiming
A
Sun
James P
JP
Snyder
Haian
H
Fu
Yuhong
Y
Du
Iestyn
I
Lewis
J David
JD
Lambeth
D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D057166:High-Throughput Screening Assays; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D054833:Isoindoles; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects; D016566:Organoselenium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism*
D001393:Azoles; D007527:Isoenzymes; D054833:Isoindoles; D008562:Membrane Glycoproteins; D016566:Organoselenium Compounds; D011994:Recombinant Proteins; D013481:Superoxides; C042986:ebselen; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1