Reprofiled drug targets ancient protozoans: drug discovery for parasitic diarrheal diseases

Gut Microbes. Jan-Feb 2013;4(1):66-71. doi: 10.4161/gmic.22596. Epub 2012 Nov 8.

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.

Keywords: Cryptosporidium parvum; Entamoeba; Giardia; auranofin; diarrheal diseases; drug discovery; high throughput screen; orphan drug; protozoan parasites; thioredoxin reductase.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Antiprotozoal Agents / isolation & purification*
  • Antiprotozoal Agents / pharmacology*
  • Auranofin / isolation & purification*
  • Auranofin / pharmacology*
  • Cryptosporidium parvum / drug effects
  • Drug Discovery / methods*
  • Entamoeba histolytica / drug effects*
  • Enzyme Inhibitors / isolation & purification
  • Enzyme Inhibitors / pharmacology
  • Giardia lamblia / drug effects
  • High-Throughput Screening Assays*
  • Thioredoxin-Disulfide Reductase / antagonists & inhibitors

Substances

  • Antiprotozoal Agents
  • Enzyme Inhibitors
  • Auranofin
  • Thioredoxin-Disulfide Reductase