Teaching Old Drugs New Tricks

Anjan Debnath, a leader of the CDIPD Amoebozoa Core, conducts his groundbreaking reseach in the UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences.

Drug discovery for amebiasis, caused by the intestinal parasite Entamoeba histolytica, has been hindered by the absence of real assay development suitable for high-throughput screening. To accelerate the identification of new drug leads for amebiasis, we developed a novel high-throughput screen that could be conducted in an oxygen-free environment in microtiter plates, mimicking ameba's natural habitat. A screen of a library with 910 compounds, consisting of FDA-approved drugs and unapproved bioactive compounds, identified auranofin as the most potent of all and the drug was 10 times more effective in culture than metronidazole. We selected auranofin for follow-up studies because auranofin is an FDA-approved drug and has been in clinical use to treat rheumatoid arthritis since 1985, secondly, this drug is taken orally, and finally it is relatively cheap. In the animal model of amebic colitis a single oral dose of 1 mg/kg/day for 7 days significantly reduced the number of parasites and the detrimental host inflammatory response but not by similar dose of metronidazole, the current drug of choice. Similarly, a low dose of oral auranofin for 7 days significantly reduced the liver damage in the animal model of amebic liver abscess but same dose of metronidazole had no effect on liver abscess progression. Based on these findings, auranofin has now received an Orphan Drug status from the FDA for the treatment of amebiasis. Since the drug is off-patent and has been in clinical use for more than 25 years, the cost and development time for this "repurposed drug" can be significantly reduced. This cost saving is important in the context of the disease afflicting the poor.

Since our discovery of auranofin as a new drug lead for E. histolytica our collaborators looked at its efficacy for related organisms and showed efficacy of auranofin against other parasites such as diarrheal parasite Giardia infecting 280 million people worldwide each year, another diarrheal parasite Cryptosporidium affecting 500 million people, sexually-transmitted parasite Trichomonas vaginalis infecting 174 million people worldwide every year, adult worm Brugia that causes disfiguring lymphatic filariasis, also known as elephantiasis and infecting 128 million people and another adult worm Onchocerca that causes river blindness and infects 37 million people. Altogether, auranofin showed efficacy against these parasites infecting about 1 billion people worldwide.

Auranofin is now poised for clinical trials in Bangladesh for amebiasis and giardiasis. If successful in clinical trial, auranofin could be the first new drug with a defined target for the treatment of amebiasis and giardiasis affecting more than 300 million people each year.

by Dr. Anjan Debnath, UCSD