Discovery of novel antigiardiasis drug candidates.

Therapeutic Approaches
Medicinal Chemistry

Abstract

Giardiasis is a severe intestinal parasitic disease caused by Giardia lamblia, which inflicts many people in poor regions and is the most common parasitic infection in the United States. Current standard care drugs are associated with undesirable side effects, treatment failures, and an increasing incidence of drug resistance. As follow-up to a high-throughput screening of an approved drug library, which identified compounds lethal to G. lamblia trophozoites, we have determined the minimum lethal concentrations of 28 drugs and advanced 10 of them to in vivo studies in mice. The results were compared to treatment with the standard care drug, metronidazole, in order to identify drugs with equal or better anti-Giardia activities. Three drugs, fumagillin, carbadox, and tioxidazole, were identified. These compounds were also potent against metronidazole-resistant human G. lamblia isolates (assemblages A and B), as determined in in vitro assays. Of these three compounds, fumagillin is currently an orphan drug used within the European Union to treat microsporidiosis in immunocompromised individuals, whereas carbadox and tioxidazole are used in veterinary medicine. A dose-dependent study of fumagillin in a giardiasis mouse model revealed that the effective dose of fumagillin was ∼ 100-fold lower than the metronidazole dose. Therefore, fumagillin may be advanced to further studies as an alternative treatment for giardiasis when metronidazole fails.

Authors

Kulakova, Liudmila; Galkin, Andrey; Chen, Catherine; Southall, Noel; Marugan, Juan; Zheng, Wei; Herzberg, Osnat;

Keywords

  • Aminopeptidases/ antagonists & inhibitors
  • Aminopeptidases/ chemistry
  • Animals
  • Antiprotozoal Agents/ chemistry
  • Antiprotozoal Agents/ pharmacology
  • Axenic Culture
  • Carbadox/ chemistry
  • Carbadox/ pharmacology
  • Cyclohexanes/ chemistry
  • Cyclohexanes/ pharmacology
  • Drug Discovery
  • Drug Resistance
  • Fatty Acids, Unsaturated/ chemistry
  • Fatty Acids, Unsaturated/ pharmacology
  • Giardia lamblia/ drug effects
  • Giardia lamblia/ growth & development
  • Giardiasis/ drug therapy
  • Giardiasis/ parasitology
  • Glycoproteins/ antagonists & inhibitors
  • Glycoproteins/ chemistry
  • High-Throughput Screening Assays
  • Humans
  • Inhibitory Concentration 50
  • Metronidazole/ pharmacology
  • Mice
  • Parasitic Sensitivity Tests
  • Sesquiterpenes/ chemistry
  • Sesquiterpenes/ pharmacology
  • Species Specificity
  • Structure-Activity Relationship
  • Thiazoles/ chemistry
  • Thiazoles/ pharmacology
  • Trophozoites/ drug effects
  • Trophozoites/ growth & development

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