SALT LAKE CITY–A team of researchers from the United States and Mexico has identified a promising therapy for amebiasis, an intestinal infection caused by the parasite Entamoeba histolytica. After developing a new rapid drug screening technique, the scientists discovered that a gold-containing drug called auranofin may be effective in treating amebiasis. According to a study published online May 20, 2012 in Nature Medicine, auranofin is 10 times more potent than the existing treatment for these serious parasitic infections.
Amebiasis is the fourth leading cause of death due to parasitic infections worldwide, affecting an estimated 50 million people and resulting in approximately 70,000 deaths each year. An antibiotic called metronidazole is currently the treatment of choice for amebiasis. However, metronidazole is associated with both undesirable side effects and an increasing concern for drug resistance.
“Until now, screening to identify new treatments for amebiasis has been limited by the lengthy amount of time needed to process traditional assays,” says Amy Barrios, Ph.D., assistant professor of medicinal chemistry at the University of Utah College of Pharmacy and a study contributor.
In this study, researchers from the University of California, San Francisco, developed an automated, high-throughput screen to rapidly and more efficiently screen chemical libraries, including a series of auranofin analogs synthesized by Barrios and University of Utah researchers, for compounds with activity against Entamoeba histolytica (E. histolytica). Using this new technology, the scientists identified auranofin and one if its derivatives as potential drug candidates, with a tenfold greater ability to kill E. histolytica than metronidazole. Scientists from the University of California, San Diego, and the Center for Research and Advanced Studies of the National Polytechnic Institute in Mexico City found that auranofin was effective in reducing the number of parasites, the host inflammatory response, and the extent of liver damage in animal models of amebiasis.
Auranofin is a U.S. Food and Drug Administration-approved, gold-containing drug that has been used in the treatment of rheumatoid arthritis for many years. Recent studies have shown that auranofin may also be useful against a variety of other parasitic infections, including malaria.
“Since auranofin is already approved for human use, it may be possible to quickly and cost-effectively repurpose the drug to treat amebiasis,” says Barrios. “Shortening the development timeline for a new amebiasis treatment could have a significant impact on public health.”
Although auranofin has been in clinical use for 25 years, its mechanism of action is still poorly understood. In this study, the researchers found that auranofin likely targets an E. histolytica enzyme known as thioredoxin reductase (TrxR). TrxR plays a critical role in detoxifying the damaging reactive oxygen molecules produced by the immune system in response to parasitic invasion. By inhibiting TrxR, auranofin seems to enhance the sensitivity of E. histolytica to oxygen-mediated killing.
Based on the findings of this study, auranofin has been granted Orphan-Drug Status from the FDA for the treatment of amebiasis. The next phase of research will focus on human clinical trials.
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