title: Potent antitrypanosomal activities of heat shock protein 90 inhibitors in vitro and in vivo.
abstract: African sleeping sickness, caused by the protozoan parasite Trypanosoma brucei, is universally fatal if untreated, and current drugs are limited by severe toxicities and difficult administration. New antitrypanosomals are greatly needed. Heat shock protein 90 (Hsp90) is a conserved and ubiquitously expressed molecular chaperone essential for stress responses and cellular signaling. We investigated Hsp90 inhibitors for their antitrypanosomal activity. Geldanamycin and radicicol had nanomolar potency in vitro against bloodstream-form T. brucei; novobiocin had micromolar activity. In structure-activity studies of geldanamycin analogs, 17-AAG and 17-DMAG were most selective against T. brucei as compared to mammalian cells. 17-AAG treatment sensitized trypanosomes to heat shock and caused severe morphological abnormalities and cell cycle disruption. Both oral and parenteral 17-DMAG cured mice of a normally lethal infection of T. brucei. These promising results support the use of inhibitors to study Hsp90 function in trypanosomes and to expand current clinical development of Hsp90 inhibitors to include T. brucei.
authors: Department of Pharmacology and Molecular Sciences, The Johns Hopkins UniversitySchool of Medicine, Baltimore, MD, USA.
authors: Kirsten J
authors: KJ
authors: Meyer
authors: Theresa A
authors: TA
authors: Shapiro
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D047029:Lactams, Macrocyclic / Q000494:pharmacology / Q000627:therapeutic use; D018942:Macrolides / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D009675:Novobiocin / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D016896:Treatment Outcome; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology*; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D000981:Antiprotozoal Agents; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018942:Macrolides; D009675:Novobiocin; C035359:monorden; C001277:geldanamycin
keywords: 17-AAG; 17-DMAG; Hsp90; Trypanosoma brucei; cell cycle; drug; geldanamycin; human African trypanosomiasis; inhibitor; kinetoplast
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