Drug screening and discovery against the human intestinal parasite Entamoeba histolytica

Entamoeba histolytica is a protozoan amoeba and human parasite which causes the disease amoebiasis, also known as amoebic colitis. The World Health Organization estimates that at any given time approximately 50 million people worldwide are hosts to E. histolytica parasites, resulting in an estimated 50,000 to 70,000 deaths each year. Unfortunately, due to the fecal-oral transmission route of E. histolytica, it most severely affects socieoeconomically vulnerable populations experiencing difficulty in accessing clean water and food. For many years this disease has been treated using the nitroimidazole drug metronidazole. However, notable drawbacks to this drug do exist, such as strong adverse effects and the need for followup treatments in order to eliminate the transmissible cyst stage of E. histolytica. Due to these and other factors, the search for new and different drugs that kill E. histolytica remains urgent and ongoing.Here I present two studies in which my co-authors and I contributed to this search using two different screening approaches, allowing us to identify multiple highly potent anti-amoebic compounds with various favorable properties for further development as potential treatments for amoebiasis. In the first study, we conducted a small, targeted screen of FDA-approved kinase inhibitor drugs for their ability to kill E. histolytica trophozoites in vitro and identified potent activity among a number of candidates. Using computational analyses, we were then able to further refine the results of this initial screen and identify additional drugs with even higher potency, as well as additional desirable properties such as inhibition of infective Entamoeba cysts. In the second study, we collaborated with Janssen pharmaceuticals to obtain an 80,000-member chemical library, and used it to conduct a high-throughput screen for inhibitors of E. histolytica growth and survival. From this screen we identified a new highly-potent inhibitor molecule, as well as several additional, structurally-related inhibitors. Further experimentation showed this compound to possess desirable properties such as inhibition of Entamoeba cysts, and non-toxicity to cultured human cells. Together these studies document the discovery of two novel families of highly-effective anti-amoebic drugs with strong potential for further development as treatments against this devastating diseas