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

Smith, Susan; Min, Jaeki; Ganesh, Thota; Diebold, Becky A.; Kawahara, Tsukasa; Zhu, Yerun; McCoy, James; Sun, Aiming; Snyder, James P.; Fu, Haian; Du, Yuhong; Lewis, Iestyn; Lambeth, J. David

doi:10.1016/j.chembiol.2012.04.015

Cited by 96 publications

(129 citation statements)

References 79 publications

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“…Administration of the NOX2 inhibitor apocynin to asthmatic patients led to decreased H 2 O 2 levels in exhaled breath condensates (284). In guinea pigs, ebselen, a potent NOX2 inhibitor (276,338), was able to improve the ovalbumin-induced asthmatic inflammatory responses, consistent with a role for NOX2 (276,338). However, other evidence suggests that NOX2 may have a protective role in asthma, at least in mice.…”

Section: Nox2 As a Target For Drug Developmentmentioning

confidence: 82%

“…A HTS was designed to monitor this interaction via fluorescence polarization. In this screen (276), the binding of a synthetic, rhodamine-labeled peptide corresponding to the PRD of p22phox (rho-PRD) to recombinant glutathione-S-transferase-p47-bis-SH3 showed increased fluorescence polarization, while displacement of rho-PRD by the unlabeled PRD caused decreased signals. Using this principle, 230,000 compounds were screened; dose dependencies were carried out among initial hits; and 55 compounds were identified for confirmation in activity assays, resulting in the identification of 3-5 bona fide inhibitors.…”

Section: Screens For Disruption Of Subunit Interactionsmentioning

confidence: 99%

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NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

Diebold

Smith

Yang

et al. 2015

Antioxidants & Redox Signaling

106

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Significance: NOX2 is important for host defense, and yet is implicated in a large number of diseases in which inflammation plays a role in pathogenesis. These include acute and chronic lung inflammatory diseases, stroke, traumatic brain injury, and neurodegenerative diseases, including Alzheimer's and Parkinson's Diseases. Recent Advances: Recent drug development programs have targeted several NOX isoforms that are implicated in a variety of diseases. The focus has been primarily on NOX4 and NOX1 rather than on NOX2, due, in part, to concerns about possible immunosuppressive side effects. Nevertheless, NOX2 clearly contributes to the pathogenesis of many inflammatory diseases, and its inhibition is predicted to provide a novel therapeutic approach. Critical Issues: Possible side effects that might arise from targeting NOX2 are discussed, including the possibility that such inhibition will contribute to increased infections and/or autoimmune disorders. The state of the field with regard to existing NOX2 inhibitors and targeted development of novel inhibitors is also summarized. Future Directions: NOX2 inhibitors show particular promise for the treatment of inflammatory diseases, both acute and chronic. Theoretical side effects include pro-inflammatory and autoimmune complications and should be considered in any therapeutic program, but in our opinion, available data do not indicate that they are sufficiently likely to eliminate NOX2 as a drug target, particularly when weighed against the seriousness of many NOX2-related indications. Model studies demonstrating efficacy with minimal side effects are needed to encourage future development of NOX2 inhibitors as therapeutic agents. Antioxid. Redox Signal. 23,

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Section: Nox2 As a Target For Drug Developmentmentioning

confidence: 82%

Section: Screens For Disruption Of Subunit Interactionsmentioning

confidence: 99%

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

Diebold

Smith

Yang

et al. 2015

Antioxidants & Redox Signaling

106

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“…The activity of NOX2, the most intensively studied NOX, is regulated by a protein complex containing p22phox, p40phox, p47phox, p67phox, and the small GTPase RAC1. NOX1, NOX3, and NOX4 also require p22phox, whereas the activity of NOX5, DUOX1, and DUOX2 is independent of this regulator (Smith et al 2012). To date, three members of the NOX family are known in fungi.…”

mentioning

confidence: 99%

New Insights Into the Roles of NADPH Oxidases in Sexual Development and Ascospore Germination in Sordaria macrospora

et al. 2014

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NADPH oxidase (NOX)-derived reactive oxygen species (ROS) act as signaling determinants that induce different cellular processes. To characterize NOX function during fungal development, we utilized the genetically tractable ascomycete Sordaria macrospora. Genome sequencing of a sterile mutant led us to identify the NADPH oxidase encoding nox1 as a gene required for fruiting body formation, regular hyphal growth, and hyphal fusion. These phenotypes are shared by Δnor1, lacking the NOX regulator NOR1. Further phenotypic analyses revealed a high correlation between increased ROS production and hyphal fusion deficiencies in Δnox1 and other sterile mutants. A genome-wide transcriptional profiling analysis of mycelia and isolated protoperithecia from wild type and Δnox1 revealed that nox1 inactivation affects the expression of genes related to cytoskeleton remodeling, hyphal fusion, metabolism, and mitochondrial respiration. Genetic analysis of Δnox2, lacking the NADPH oxidase 2 gene, Δnor1, and transcription factor deletion mutant Δste12, revealed a strict melanin-dependent ascospore germination defect, indicating a common genetic pathway for these three genes. We report that gsa3, encoding a G-protein a-subunit, and sac1, encoding cAMP-generating adenylate cyclase, act in a separate pathway during the germination process. The finding that cAMP inhibits ascospore germination in a melanin-dependent manner supports a model in which cAMP inhibits NOX2 activity, thus suggesting a link between both pathways. Our results expand the current knowledge on the role of NOX enzymes in fungal development and provide a frame to define upstream and downstream components of the NOX signaling pathways in fungi. D URING sexual reproduction, filamentous fungi generate complex fruiting bodies that contain and protect meiosporangia. We used the ascomycetous model fungus Sordaria macrospora to identify genes directly involved in fruiting body development (Kück et al. 2009;Engh et al. 2010;Kück et al. 2009). Due to its homothallic life style, S. macrospora is able to complete the sexual life cycle without the mating of strains with opposite sex, and therefore, fruiting body-deficient mutants can be recognized directly without the need for crossing experiments. In earlier work, we generated sterile mutants showing a developmental block after formation of young fruiting bodies (protoperithecia), but being unable to generate mature perithecia, and referred to these mutants as pro. Recently, we have applied next-generation genome re-sequencing to identify the genes affected in some of these mutants . Based on this approach, we now have characterized mutant pro32 and show that it carries a mutation in the nox1 gene encoding NAPDH oxidase 1 (NOX1).NADPH oxidase (NOX) enzymes are transmembrane proteins that are highly conserved among eukaryotes and produce reactive oxygen species (ROS) through the oxidation of NADPH (Lambeth 2004;Kawahara and Lambeth 2007). ROS have long been recognized as damaging agents due to uncontrolled oxidizing re...

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“…Another screen, conducted using an activity-based probe for inhibitors of the APD, identified ebselen, a FDA-approved compound, which reduced tissue pathology in a mouse infection model 129 . Notably, ebselen has also been reported to block NADPH oxidase 1 activity 130 , a function that could contribute to a decrease in toxin-induced production of reactive oxygen species. Similarly, N-acetylcysteine, an FDA-approved antioxidant, prevented TcdB-induced tissue damage in a colonic explant model 126 .…”

Section: The Large Clostridial Toxins Tcda and Tcdbmentioning

confidence: 99%

Clostridium difficile Infection

Wilcox

2015

Infectious Disease Clinics of North America

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

Cited by 96 publications

References 79 publications

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

New Insights Into the Roles of NADPH Oxidases in Sexual Development and Ascospore Germination in Sordaria macrospora

Clostridium difficile Infection

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