Thioredoxin reductase and its role as a new drug target

Abstract

Amebiasis causes approximately 70,000 deaths annually and is the fourth cause of death from protozoan parasites in the world. It is treated primarily with metronidazole, which has adverse side effects and is mutagenic and carcinogenic. Also, emergence of metronidazole resistance is an increasing concern. Unfortunately, better therapeutic alternatives are lacking. Drug discovery efforts have led to reprofiling of older FDA-approved drugs. This approach is advantageous because safety and pharmacokinetic effects in humans have already been confirmed clinically and approved for use. In high-throughput screening studies, we have recently demonstrated that auranofin, a gold-containing compound that was originally approved to treat rheumatoid arthritis, has activity against trophozoites of Entamoeba histolytica, the causative agent of amebiasis. The antiparasitic activity of auranofin [1, 2] likely stems from the monovalent gold that readily dissociates and inhibits E. histolytica thioredoxin reductase, which is the only thiol-dependent flavoreductase present in this protozoan parasite [3–5]. Auranofin has also shown promising in vitro activity against metronidazole- resistant Giardia (Lars Eckmann, personal communication), Plasmodium falciparum [6], and Schistosoma mansoni [1]. Altogether, this evidence suggests that auranofin has the potential to become a broad-spectrum alternative therapeutic agent for diseases that represent a huge global burden.