New drug target in protozoan parasites: the role of thioredoxin reductase.

Rosa M Andrade,Sharon L Reed

doi:10.3389/fmicb.2015.00975

Rosa M Andrade, Sharon L Reed

Open Access

https://doi.org/10.3389/fmicb.2015.00975

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Abstract

Amebiasis causes approximately 70,000 deaths annually and is the third cause of death due to parasites worldwide. It is treated primarily with metronidazole, which has adverse side effects, is mutagenic and carcinogenic, and emergence of resistance is an increasing concern. Unfortunately, better therapeutic alternatives are lacking. Re-purposing of older FDA approved drugs is advantageous to drug discovery since safety and pharmacokinetic effects in humans are already known. In high throughput screening studies, we recently demonstrated that auranofin, a gold containing compound originally approved to treat rheumatoid arthritis, has activity against trophozoites of E. histolytica, the causative agent of amebiasis. Auranofin's anti-parasitic activity is attributed to its monovalent gold molecule that readily inhibits E. histolytica thioredoxin reductase. This anti-oxidant enzyme is the only thiol-dependent flavo-reductase present in E. histolytica. Auranofin has also shown promising activity against other protozoans of significant public health importance. Altogether, this evidence suggests that auranofin has the potential to become a broad spectrum alternative therapeutic agent for diseases with a large global burden.

Highlights

The three major causes of protozoal diarrhea worldwide are E. histolytica, G. lamblia, and Cryptosporidium sp., which cause significant morbidity and mortality in developing and developed countries (Fletcher et al, 2012)
High levels of these reactive nitrogen species (RNS) might inhibit E. histolytica growth in vitro (Arias et al, 2012), the parasite is able to survive and multiply during tissue invasion. This suggests that E. histolytica detoxification system is versatile enough to tolerate hostile environments. This versatility was recently demonstrated by E. histolytica Trx-Thioredoxin reductases (TrxRs) system ability to reduce RNS and use an alternative electron donor such as NADH (Arias et al, 2012)
Given the lack of reactive oxygen species (ROS)-dependent anti-oxidant systems and glutathione, the thioredoxin-thioredoxin reductase system is thought to constitute a major part of the antioxidant defense in this organism. It consists of a soluble dimeric FAD containing NADPH-dependent disulfide reductase, which contains a two 35-kDa subunits and a partially purified 12-kDa protein; a putative thioredoxin, a low molecular weight thioredoxin reductase (TrxR), which has 75% identity to the E. coli thioredoxin reductase (Brown et al, 1998), and a thioredoxinperoxidase

Summary

Introduction

The three major causes of protozoal diarrhea worldwide are E. histolytica, G. lamblia, and Cryptosporidium sp., which cause significant morbidity and mortality in developing and developed countries (Fletcher et al, 2012). High molecular weight (H-TrxR) enzymes that contain a redox active center (motif CXXXXC) in the FAD binding domain. Low molecular weight (L-TrxR) enzymes that contain a redox active disulfide (motif CXXC) in the NADPH domain.

Results

Conclusion