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NOX enzymes as novel targets for drug development

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Abstract

The members of the NOX/DUOX family of NADPH oxidases mediate such physiologic functions as host defense, cell signaling, and thyroid hormone biosynthesis through the generation of reactive oxygen species (ROS), including superoxide anion and hydrogen peroxide. Moreover, ROS are involved in a broad range of fundamental biochemical and cellular processes, and data accumulated in recent years indicate that the NOX enzymes comprise one of the most important biological sources of ROS. Given the high biochemical reactivity of ROS, it is not surprising that they have been implicated in a wide variety of pathologies and diseases. Prominent among the settings that feature ROS-mediated tissue injury are disorders associated with inflammation, aging, and progressive degenerative changes in cells and organ systems, and it appears that essentially no organ system is exempt. Among the disorders currently believed to be mediated at least in part by NOX-derived ROS are hypertension, aortic aneurysm, myocardial infarction (and other ischemia–reperfusion disorders), pulmonary fibrosis and hypertension, amyotropic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, ischemic stroke, diabetic nephropathy, and renal cell carcinoma. Several small-molecule and peptide inhibitors of the NOX enzymes have been useful in experimental studies, but issues of specificity, potency, and toxicity militate against any of the existing published compounds as candidates for drug development. Given the broad array of disease targets documented in recent work, the time is here for vigorous efforts to develop clinically useful inhibitors of the NOX enzymes. As most (though not all) NOX-related diseases appear to be mediated by a single member of the NOX family, agents with isoform specificity will be preferred, although broadly active NOX inhibitors may prove to be useful in some settings.

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Acknowledgments

This work was supported by grants from the US National Institutes of Health (CA105116 and CA084138 awarded to JDL; R01 AI020866 awarded to RAC) and the Swiss National Foundation (100A0-103725 awarded to K-HK).

Declaration of potential conflict of interest

JDL, KHK and RAC are among the founding scientists of the start-up company GenKyoTex, SA, which is developing NOX inhibitors.

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Authors and Affiliations

  1. Emory University, Atlanta, GA, USA

    J. David Lambeth

  2. University of Geneva, Geneva, Switzerland

    Karl-Heinz Krause

  3. University of Texas Health Science Center, San Antonio, TX, USA

    Robert A. Clark

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  1. J. David Lambeth
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  2. Karl-Heinz Krause
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Correspondence to J. David Lambeth.

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Lambeth, J.D., Krause, KH. & Clark, R.A. NOX enzymes as novel targets for drug development. Semin Immunopathol 30, 339–363 (2008). https://doi.org/10.1007/s00281-008-0123-6

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