NADPH oxidase inhibitors: a decade of discovery from Nox2ds to HTS

Abstract

NADPH oxidases (Nox) are established as major sources of reactive oxygen species (ROS). Over the past two decades, Nox-derived ROS have emerged as pivotal in the development of myriad diseases involving oxidative stress. In contrast, Nox are also involved in signaling mechanisms necessary for normal cell function. The study of these enzymes in physiological and pathophysiological conditions is made considerably more complex by the discovery of 7 isoforms: Nox1 through 5 as well as Duox1 and 2, each with its own specific cytosolic components, regulatory control mechanisms, subcellular localization and/or tissue distribution. A clear understanding of the role individual isoforms play in a given system is hindered by the lack of isoform-specific inhibitors. In animal models, knockdown or knockout methodologies are providing definitive answers to perplexing questions of the complex interplay of multiple Nox isoforms in cell and tissue signaling. However, the complex structures and interactions of these heteromeric isozymes predict pleiotropic actions of the Nox subunits and thus suppression of these proteins is almost certain to have untoward effects. Thus, as both therapies and pharmacological tools, molecule-based inhibitors continue to prove extremely useful and rational in design. Unfortunately, many of the available inhibitors have proven non-specific, falling into the category of scavengers or inhibitors of more than one source of ROS. Here, we will review some of the efforts that have been undertaken to develop specific inhibitors of NADPH oxidase over the past decade, from the peptidic inhibitor Nox2ds-tat to more recent small molecule inhibitors that have emerged from high-throughput screening campaigns.

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

“…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).…”

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

“…Since the 1990s, a variety of NOXtargeted inhibitory peptides representing many regions of the NOX subunit have been developed (47,56,57,70,71) and employed in vitro, although to our knowledge, only one of these has been tested in vivo (47). gp91(NOX2)ds-tat is an 18-amino-acid peptide that includes a part of the B-loop of NOX2 that was designed to block the interaction between NOX2 and its regulatory subunit p47phox.…”

Discovery of GSK2795039, a Novel Small Molecule NADPH Oxidase 2 Inhibitor

“…Throughout the last decade, efforts to validate the relative contribution of specific NOX enzymes to either normal physiological processes or to pathological states have been made primarily via the characterization of genetic knockout animals or with the use of peptide-based inhibitors (12,37). However, both approaches have different caveats such as the potential for compensatory mechanisms in constitutive knockout mice and the limited biodistribution and efficacy of peptides.…”