Glutathione metabolism of filarial worms: A vulnerable target for the designand synthesis of new antifilarial agents.

摘要

The main problem regarding the chemotherapy of filariasis is that no safeand effective drug is available yet to combat the adult human filarial worms. One of the main reasonsis the prolonged existence, i.e. survival of filarial worms in mammalian hosts for many years, and havinga very strong antioxidant system. Glutathione (GSH) has been identified as an important part of the antioxidantsystem of many, if not all, living cells and, together with glutathione reductase (GR), it maintainsthe correct intracellular redox balance. It protects the cell against oxidative damage by non-enzymaticscavenging of free radicals and by enzymatic neutralization of toxic hydrogen peroxide, lipid hydroperoxides,and derivatives by glutathione-dependent peroxidases (GPXs) and glutathione-S-transferases (GSTs). Workin this direction reveals that filarial worms can synthesize and recycle GSH, and its depletion may beuseful in chemotherapeutic situations in which the cells to be killed and the cells to be spared havesubstantially different quantitative requirements for GSH. All normal mammalian cells have a considerableamount of GSH, whereas filarial worms may have GSH concentrations close to that required for their survivaland, therefore, a little manipulation of the glutathione metabolism of filarial worms may have drasticconsequences. The present review details the application of the glutathione metabolism of filarial wormsas a target for the design and synthesis of new antifilarial agents.