The redox biology of schistosome parasites and applications for drug development

Abstract

Schistosomiasis caused by Schistosoma spp. is a serious public health concern, especially in sub-Saharan Africa. Praziquantel is the only drug currently administrated to treat this disease. However, praziquantel-resistant parasites have been identified in endemic areas and can be generated in the laboratory. Therefore, it is essential to find new therapeutics. Antioxidants are appealing drug targets. In order to survive in their hosts, schistosomes are challenged by reactive oxygen species from intrinsic and extrinsic sources. Schistosome antioxidant enzymes have been identified as essential proteins and novel drug targets and inhibition of the antioxidant response can lead to parasite death. Because the organization of the redox network in schistosomes is significantly different from that in humans, new drugs are being developed targeting schistosome antioxidants. In this paper the redox biology of schistosomes is discussed and their potential use as drug targets is reviewed. It is hoped that compounds targeting parasite antioxidant responses will become clinically relevant drugs in the near future.

Figure 1

Structures of antischistosomal drugs previously and currently used in clinical practice.

Figure 2

Enzymes involved in the glutathione metabolism. Synthesis of glutathione. 1: condensation of L-cysteine (C) and L-glutamate (γE) by γ-glutamate cysteine ligase (CGL) to form the dipeptide γ-glutamylcysteine (γEC). 2: condensation of γ-glutamylcysteine (γEC) and glycine (G) by glutathione synthase (GS) to yield GSH (γECG). Detoxification processes. 3: conjugation of GSH to electrophilic compounds (X) catalyzed by glutathione S-transferase (GST). 4: cleavage of γ-glutamate from GSH or GSH conjugates (γECxG) by γ-glutamyl transferase (γGT) yielding respectively CG and CxG. 5: cleavage of glycine from GSH or GSH conjugates by phytochelatin synthase (PCS) to give respectively phytochelatins (γ(EC)_nG) and γEC-X. 6: reduction of H₂O₂ and lipid hydroperoxides (LOOH) to water and the corresponding alcohols (LOH) and water with GSH by glutathione peroxidase and peroxiredoxins.

Figure 3

The antioxidant protein network in Schistosoma mansoni. TGR catalyzes deglutathionylation reactions of proteins and peptides⁽¹⁾. In addition, TGR not only reduces GSSG and oxidized Trx but also low molecular weight compounds (e.g., hydrogen peroxide)⁽²⁾ utilizing NADPH. Prx proteins can receive electrons from either Trx or GSH to neutralize H₂O₂ and lipid peroxides.

Figure 4

Assays used in high throughput drug screen. A coupled enzymatic assay was used in order to screen compounds which are able to inhibit TGR and/or Prx-2. Prx-2 catalyzes conversion of hydrogen peroxide to water utilizing GSH. The resultant GSSG from the previous reaction is recycled to GSH by TGR using NADPH. The consumption rates of NADPH were monitored with fluorescence of NADPH (excitation: 365 nm and emission: 450 nm). The figure is adapted from [198].

Figure 5

The general structure of oxidazole-2-oxides. The presence of electron-withdrawing groups at positions R₁ and R₂ are essential to the activity of oxidazole-2-oxides.

Figure 6

The function of methionine sulfoxide reductase (Msr) in the redox network of Schistosoma mansoni. Reactive oxygen species (ROS) can convert methionine (the free amino acid as shown here or in a protein) to methionine sulfoxide. This may lead to inactivation of protein function. Reduction of methionine sulfoxide and reactivation of the protein and prevention of higher oxidation states of methionine can be carried out by Msr using reduced thioredoxin (Trx_(red)) as the electron donor producing oxidized thioredoxin (Trx_(ox)). Reduction of Trx_(ox) by thioredoxin glutathione reductase (TGR) is accompanied by the consumption of NADPH.