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

Abstract

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.

In-vitro and in silico efficacy of isolated alkaloid compounds from Rauvolfia tetraphylla L. against bovine filarial parasite Setaria cervi: a drug discovery approach

“…The complete immobilization of the adult worms with [ 50% inhibition of MTT reduction by treated parasites compared to untreated controls was considered as macrofilaricidal action (Mukherjee et al 1998). The isolated compounds were also evaluated for the glutathione-Stransferase (ScGST) inhibition assay using the cytosolic fraction of adult Setaria worms using standard procedure with some modifications (Habig et al 1974;Ahmad and Srivastava 2008;Srinivasan et al 2011). Protein content was estimated by Lowry's method using bovine serum albumin (BSA) as standard (Lowry et al 1951) to find out the changes in protein content of worm homogenate in control and treated samples.…”

Biochemical characterization and peptide mass fingerprinting of two glutathione transferases from Biomphalaria alexandrina snails (Gastropoda: Planorbidae)

“…The second are GSH conjugates, which occupy both the GSH binding site and at least part of the H-site and are competitive with respect to both GSH and hydrophobic substrate. The third class of inhibitors of compounds referred to as non-substrate ligands which are noncompetitive inhibitors of GSTs [ 36 ]. In the present investigation, hematin and CB were the most potent inhibitors for BaGST2 and BaGST3, with IC 50 approximately of 0.5 μM, whereas in IC 50 values of S-hexyl-GSH, S-butyl-GSH, and S-P-bromobenzyl-GSH, BSP are approximatly100-fold higher but remain within the range reported for other GSTs [ 35 , 37 ].…”