Nox Inhibitors & Therapies: Rational Design of Peptidic and Small Molecule Inhibitors

Abstract

Oxidative stress-related diseases underlie many if not all of the major leading causes of death in United States and the Western World. Thus, enormous interest from both academia and pharmaceutical industry has been placed on the development of agents which attenuate oxidative stress. With that in mind, great efforts have been placed in the development of inhibitors of NADPH oxidase (Nox), the major enzymatic source of reactive oxygen species and oxidative stress in many cells and tissue. The regulation of a catalytically active Nox enzyme involves numerous protein-protein interactions which, in turn, afford numerous targets for inhibition of its activity. In this review, we will provide an updated overview of the available Nox inhibitors, both peptidic and small molecules, and discuss the body of data related to their possible mechanisms of action and specificity towards each of the various isoforms of Nox. Indeed, there have been some very notable successes. However, despite great commitment by many in the field, the need for efficacious and well-characterized, isoform-specific Nox inhibitors, essential for the treatment of major diseases as well as for delineating the contribution of a given Nox in physiological redox signalling, continues to grow.

Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure

“…6 This is relevant from a therapeutic perspective because isoform-selective Nox inhibitors are currently being developed. 8 Previous work suggested an involvement of Nox1 in the genesis of AngII-dependent hypertension. Mice globally deficient in p47 phox , a subunit required for both Nox1 and Nox2 function, display a reduced hypertensive response to AngII, 9 as do global Nox1 knockout (KO) mice, 10 whereas vascular smooth muscle–targeted Nox1 transgenic mice develop exaggerated AngII-induced hypertension.…”

Crossroads between peripheral atherosclerosis, western-type diet and skeletal muscle pathophysiology: emphasis on apolipoprotein E deficiency and peripheral arterial disease

“…Exciting recent research is focusing on the pharmacological inhibition of Noxs by small molecule inhibitors for counteracting the atherothrombotic process [240–243]. However, most animal studies employing small molecule inhibitors such as the Vaso-pharm triazolo pyrimidine derivatives, apocynin and diphenyleneiodonium either lack specificity or have adverse effects [241, 244, 245]. Recently ebselen and its analogues were identified as specific inhibitors of Nox2 and of Nox1, with the JM-77b derivative having a greater specificity for Nox2 than Nox1, Nox4 and Nox5 [240–242].…”

“…Similarly, GKT136901 and GKT137831, a pyrazolopyridine class of compounds, are specific inhibitors of both Nox1 and Nox4. Administration of the GKT137831 inhibitor has been shown to reduce liver fibrosis and diabetic atherosclerosis in animal studies [232, 241]. It is worth mentioning that such compounds are the first oral inhibitors that are in phase II clinical trials for treatment of diabetic nephropathy [241, 246].…”

“…Administration of the GKT137831 inhibitor has been shown to reduce liver fibrosis and diabetic atherosclerosis in animal studies [232, 241]. It is worth mentioning that such compounds are the first oral inhibitors that are in phase II clinical trials for treatment of diabetic nephropathy [241, 246]. However, selective inhibition of the Nox homologues is essential in order to eliminate opposing effects and complications in cardiovascular pathologies [26, 241, 247, 248].…”

“…It is worth mentioning that such compounds are the first oral inhibitors that are in phase II clinical trials for treatment of diabetic nephropathy [241, 246]. However, selective inhibition of the Nox homologues is essential in order to eliminate opposing effects and complications in cardiovascular pathologies [26, 241, 247, 248]. Collectively, although small molecule inhibitors are a promising new area, further validation of their pharmacokinetic and pharmacodynamic profile is of paramount significance so as to proceed in clinical trials [241].…”