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

Abstract

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,

Bimodal role of NADPH oxidases in the regulation of biglycan-triggered IL-1β synthesis

“…This is in agreement with the previous findings that NOX2 deficiency in mice leads to increased levels of IL-1β in the early onset of arthritis and therefore to a more severe inflammatory phenotype [35]. Moreover, NOX2-derived ROS is essential for the phagosome function and it has been considered as a barrier of sustained inflammation [56][57][58]. Hence, we hypothesize that this protective role of NOX2-generated ROS in inflammation and IL-1β production could be regulated by biglycan.…”

Glucose-6-phosphate dehydrogenase inhibition attenuates acute lung injury through reduction in NADPH oxidase-derived reactive oxygen species

“…ROS may be released from conventional sources such as neutrophils. This usually involves activation of membrane-bound NOX2, along with cytosolic members leading to the production of ROS [10,21,22]. Over-expression of NOX2 in the pulmonary system has been shown to lead to ROS generation.…”

“…This leads to production of superoxide anions for anti-microbial effects [10,21,22]. NOX family consists of several isoforms, such as NOX1, 2, 3, 4 and 5, and dual oxidases 1 and 2.…”

“…The most studied member of this family is, of course, NOX2, which consists of specialized cytosolic proteins, p47phox and p67phox, and the small regulatory proteins, all of which are translocated to the membrane upon cell stimulation for complete assembly after interaction with the membrane subunit. This leads to production of superoxide anions for anti-microbial effects [10,21,22]. NOX2 is found mainly in phagocytes such as neutrophils, but airway epithelial cells are also known to express it [7,22].…”

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

“…Numerous animal studies using genetic ablation of gp91 phox and/or p47 phox support the hypothesis that pharmacological inhibition of NOX2 may be a therapeutic strategy (15). However, complete abrogation of NOX2 is known to lead to increased infections and increased sensitivity to autoimmune disorders and should be carefully considered for such treatments.…”