Small-Molecule NOX Inhibitors: ROS-Generating NADPH Oxidases as Therapeutic Targets

Abstract

NOX NADPH oxidases are electron-transporting membrane enzymes whose primary function is the generation of reactive oxygen species (ROS). ROS produced by NOX enzymes show a variety of biologic functions, such as microbial killing, blood pressure regulation, and otoconia formation. Strong evidence suggests that NOX enzymes are major contributors to oxidative damage in pathologic conditions. Blocking the undesirable actions of NOX enzymes, therefore, is a therapeutic strategy for treating oxidative stress-related pathologies, such as ischemia/reperfusion tissue injury, and neurodegenerative and metabolic diseases. Most currently available NOX inhibitors have low selectivity, potency, and bioavailability, precluding a pharmacologic demonstration of NOX as therapeutic targets in vivo. This review has two main purposes. First, we describe a systematic approach that we believe should be followed in the search for truly selective NOX inhibitors. Second, we present a critical review of small-molecule NOX inhibitors described over the last two decades, including recently published patents from the pharmaceutical industry. Structures, activities, and in vitro/in vivo specificity of these NOX inhibitors are discussed. We conclude that NOX inhibition is a pertinent and promising novel pharmacologic concept, but that major efforts will be necessary to develop specific NOX inhibitors suited for clinical application.

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

“…Of the many enzymes that are potential therapeutic targets are Noxs. Due to this, there has been enormous interest in the development of agents that inhibit Noxs in an isoform-specific manner (91,102,194,197). Different strategies have been employed, including smallmolecule inhibitors, peptide Nox inhibitors, and siRNAS.…”

“…Newer-generation NOX inhibitors are more specific and selective. To date, two different classes of compounds have been claimed as potent selective and orally active bioavailable Nox inhibitors: pyrazolopyridines (GKT136901 and GKT137831) and triazolopyrimidine derivatives (VAS2870 and VAS3947) (39,91,102,194,197). These agents target mainly Nox1 and Nox4, and, apparently, have a few ''off-target'' side effects (22, 217).…”

Hydrogen peroxide primes heart regeneration with a derepression mechanism

“…To investigate whether there is a causal relationship between elevated Duox/Nox2 and H 2 O 2 production and cardiac regeneration, we applied diphenyleneiodonium (DPI) (10 µM) or apocynin (100 µM), widely used inhibitors of Duox/Nox enzymes [33] and examined subsequent changes in H 2 O 2 production and cardiac regeneration. We found that Hyper fluorescent signals were decreased by 50% within ~ 40 min after soaking 14 dpa Tg(myl7:Hyper) hearts in DPI-containing medium (Figure 2A-2B), while the Hyper signals remained stable in control medium containing DMSO only ( Figure 2B and Supplementary information, Figure S8A), suggesting that high concentration of H 2 O 2 likely resulted from elevated duox/nox2 expression but was not produced from mitochondria.…”

Novel Neuroinflammatory Targets in the Chronically Injured Spinal Cord

“…There are several isoforms of NADPH oxidase, differing based on their enzymatic core. For NOX2, which is expressed in most phagocytic cells, such as microglia, the core is gp91 PHOX [11]. Alternative forms include NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2, and differ in their requirements for cytosolic and membrane subunits.…”