Ebselen and Thioredoxin Systems in Human Health, Disease and Therapeutic Potential
The thioredoxin system, which is composed of thioredoxin (Trx), thioredoxinreductase (TrxR) and NADPH, is a major disulfide reductase system regulating many enzymes important in mediating cellular redox homeostasis and DNA synthesis. Recently, thiol-dependent redox systems including the thioredoxin system have emerged as anti-microbial drug targets. The selenazol ebselen [2-phenyl-1,2 benzisoselenazol-3(2H)-one], previously used in phase III clinical trials, is a lead drug for this concept. This concept is based on the difference of thioredoxin and thioredoxinreductase in structure and catalytic mechanism between mammalian and bacterial thioredoxinreductases (TrxR). Ebselen is an inhibitor of bacterial TrxR, whereas it is a substrate of mammalian TrxR. The sulfur analog of ebselen, ebsulfur, works as an inhibitor of trypanothionereductase. Treatment of ebselen and ebsulfur blocks the electron transfer of the Trx system in some microbial pathogens, resulting in the elevation of reactive oxygen species and cell death. The anti-microbial activities of ebselen and ebsulfur have been verified in the animal model and shown to be potential novel anti-microbial drugs.