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 subSaharan 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 form 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. KeywordsSchistosoma; drug development; antioxidants; glutathione; thioredoxin; thioredoxin glutathione reductase Schistosomiasis (also known as bilharzia) is caused by blood-dwelling flatworms of the genus Schistosoma. Schistosomiasis is the second most important human parasitic disease after malaria, with an estimated 200 million people infected and greater than 200,000 deaths annually in tropical and subtropical areas [1][2][3]. Nearly 800 million people are at risk of infection in seventy-two counties [1]. In addition, schistosome infections lead to largely underreported chronic disabilities and morbidities, such as caloric malnutrition, growth stunting, anemia, and poor school performance, which lead to decreased quality of life and perpetuation of poverty [1][2][3]. The chronic morbidities associated with schistosomiasis can be exacerbated by co-infections with other helminths (parasitic worms, e.g., hookworms) [4] and schistosome infections can have significant impacts on the susceptibility and transmission of other infections, e.g., HIV [5,6] and malaria [7,8], and on immune responses to childhood vaccines [9]. Furthermore, S. haematobium is considered as a group 1 carcinogen leading to the development of urinary bladder cancer [10][11][12]. Intestinal schistosomiasis has been linked to hepatocellular carcinoma and colorectal cancer [13,14] NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptFive species of Schistosoma parasitize humans including S. mansoni, S. japonicum, S. haematobium, S. intercalatum, and S. mekongi; the first three species have the widest geographic distribution whereas infections with the last two species only occur locally [15]. The life cycle of Schistosoma ssp. is complex [16,17] and is divided into sexual and asexual cycles. In the asexual cycle, eggs are released into water with feces or urine of infected individuals. Miracidia hatch from the eggs and th...

Towards an Understanding of the Function of the Phytochelatin Synthase of Schistosoma mansoni

“…We thus thought that PCS could be regulated as part of a comprehensive antioxidant GSH-dependent defense mechanism [22]. Metals have been shown to affect the transcript levels of γ-GCS in Saccharomyces cerevisiae [48] and in plants [49] and of PCS [50].…”

“…Schistosomiasis affects more than 200 million people in more than 70 tropical and sub-tropical countries and causes more than 200,000 deaths annually [20]. Chemotherapy is the major control measure for schistosomiasis and currently only a single drug, praziquantel, is available [21], [22]. Monotherapy for such a widespread and prevalent disease raises serious concerns about the selection of drug resistant parasites [21].…”

Chemoprevention of Schistosomiasis: In vitro Antiparasitic Activity of Nineteen Plant-derived and Synthetic Simple Naphthoquinones and Naphthols against Schistosoma Mansoni Adult Worms

“…The mechanism by which NAPQs exerts their in vitro schistosomicidal effect is not clear at the present time. However, it is generally recognized that mechanisms of antiparasitic activity involve modulation of parasite redox cycling (reduction and oxidation cycle of quinones in flavin enzymes such as NADPH-cytochrome P450 and mitochondrial NADH-ubiquinone oxidoreductase) and production of reactive oxygen species (ROS) leading to severe oxidative stress by oxidizing essential macromolecules, such as proteins, lipids and DNA [47,48]. Studies have shown that NAPQs are potent electrophiles and they are also capable of directly reacting with thiol groups of S. mansoni parasite proteins and glutathione resulting in inhibition of enzymes essential for parasite survival [43,49].…”

This De-Wormed World?

“…The first is by Dr. David Williams, who along with his colleagues has been developing new approaches to treat helminth infections. For example, reasoning that schistosomes are highly dependent on the production of anti-oxidants to protect themselves from host immune attack, and that schistosomes have a redox network distinctly different from our own, he has pointed out that compounds that target distinctive schistosome redox enzymes may become clinically relevant in the near future (Huang et al, 2012). Also, Dr. LoVerde, at this year’s ASP meeting, pointed out significant advances in identifying a sulfotransferase locus (SmSULT) involved in conferring resistance to the anti-schistosome drug oxamniquine.…”