NOX研究の歴史と阻害薬開発の動向

抄録

It was well known in the end of 1980s that NADPH oxidase generates superoxide as respiratory burst in phagocytes (later named as NOX2), and that its genetic mutations could be causative for chronic granulomatous disease. Since the finding of NOX1 in 1999, a catalytic subunit highly expressed in colon epithelium, seven isoforms of NOX/DUOX family (NOX1 to NOX5 and DUOX1/2) were identified. Novel cytosolic components or maturation factors have also been identified, and isoform-specific activation mechanisms have been clarified. Using genetically modified mice, reactive oxygen species derived from NOX/NADPH oxidase have been found to be involved in various physiological functions and pathogenesis in multiple tissues in the body. An age ago, reagents that were used as inhibitors of NADPH oxidase were non-specific ones like diphenyleneiodonium, a broad-spectrum flavoprotein inhibitor, 4-(2-aminoethyl)benzenesulfonyl fluoride, an inhibitor of serine proteases, or an antioxidant apocynin. In the past two decades, selective NOX inhibitors have been developed. Among them, Setanaxib (GKT137831), a NOX1/4 inhibitor, is under Phase II clinical trial in patients with primary biliary cholangitis (liver fibrosis), Type 1 Diabetes and Kidney Disease (kidney fibrosis), and idiopathic pulmonary fibrosis, suggesting its potential as a new antifibrotic agent. Thus, NOX/NADPH oxidases are expected as novel targets of pharmacotherapeutics.