title: Reprofiled drug targets ancient protozoans: drug discovery for parasitic diarrheal diseases.
abstract: Recently, we developed a novel automated, high throughput screening (HTS) methodology for the anaerobic intestinal parasite Entamoeba histolytica. We validated this HTS platform by screening a chemical library containing US Food and Drug Administration (FDA)-approved drugs and bioactive compounds. We identified an FDA-approved drug, auranofin, as most active against E. histolytica both in vitro and in vivo. Our cell culture and animal studies indicated that thioredoxin reductase, an enzyme involved in reactive oxygen species detoxification, was the target for auranofin in E. histolytica. Here, we discuss the rationale for drug development for three parasites which are major causes of diarrhea worldwide, E. histolytica, Giardia lamblia and Cryptosporidium parvum and extend our current finding of antiparasitic activity of auranofin to Entamoeba cysts, G. lamblia and C. parvum. These studies support the use of HTS assays and reprofiling FDA-approved drugs for new therapy for neglected tropical diseases.
authors.affiliation: Center for Discovery and Innovation in Parasitic Diseases, University of California, San Francisco, San Francisco, CA, USA. anjan.debnath@ucsf.edu
authors.forename: Anjan
authors.initials: A
authors.lastname: Debnath
authors.forename: Momar
authors.initials: M
authors.lastname: Ndao
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Reed
mesh_terms: D000981:Antiprotozoal Agents / Q000302:isolation & purification* / Q000494:pharmacology*; D001310:Auranofin / Q000302:isolation & purification* / Q000494:pharmacology*; D016785:Cryptosporidium parvum / Q000187:drug effects; D055808:Drug Discovery / Q000379:methods*; D004748:Entamoeba histolytica / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology; D016829:Giardia lamblia / Q000187:drug effects; D057166:High-Throughput Screening Assays; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D001310:Auranofin; D013880:Thioredoxin-Disulfide Reductase
keywords: Cryptosporidium parvum; Entamoeba; Giardia; auranofin; diarrheal diseases; drug discovery; high throughput screen; orphan drug; protozoan parasites; thioredoxin reductase