Inhibition of Filarial Glutathione-S-transferase by various classes of compounds and their evaluation as novel antifilarial agents

Glutathione S-transferase(s); GST(s) (E.C. 2.5.1.18) are a large family of multifunctional dimeric enzymes that conjugate reduced glutathione to electrophilic centres in hydrophobic organic compounds. GST(s) represent the major class of detoxifying enzymes from parasitic helminths. The GST enzymatic activity has been described in the adult and larval stages of helminths. Several forms and isoforms of the enzyme have been purified and GST genes have also been isolated and expressed as recombinant proteins. The helminth GST(s) participate in detoxification of lipid hydroperoxides and cytotoxic carbonyl compounds produced by oxygen-reactive intermediates (ORIs). The ORIs can come from the endogenous parasite metabolism or from the host immune system. The helminth GST(s) are able to conjugate glutathione to xenobiotic compounds or to bind to the anthelminth drugs. GST is usually found to be localized near to host-parasite interface. This enzyme has been identified as a potentially vulnerable target in immunotherapy and chemotherapy of parasitic diseases. The most effective drug candidates are those based on inhibitors of GST. In the present study, purified GST from cytosolic fraction of bovine filarial worms Setaria cervi was inhibited in a concentration dependent fashion by various compounds such as hemin, ethacrynic acid, S-hexylglutathione, quercetin, cibacron blue, lithocholate sulfate and ellagic acid. Cytosolic GST was inhibited to varying degrees by each inhibitor. In this context, the possible physiological significance of the observed results has been discussed.