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	Kirsten J Meyer, Theresa A Shapiro
Journal	The Journal of infectious diseases (J Infect Dis) Vol. 208 Issue 3 Pg. 489-99 (Aug 01 2013) ISSN: 1537-6613 [Electronic] United States
PMID	23630365 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Antiprotozoal Agents Benzoquinones Enzyme Inhibitors HSP90 Heat-Shock Proteins Lactams, Macrocyclic Macrolides Novobiocin monorden geldanamycin
Topics	Animals Antiprotozoal Agents (pharmacology, therapeutic use) Benzoquinones (pharmacology, therapeutic use) Disease Models, Animal Enzyme Inhibitors (pharmacology, therapeutic use) Female HSP90 Heat-Shock Proteins (antagonists & inhibitors) Lactams, Macrocyclic (pharmacology, therapeutic use) Macrolides (pharmacology, therapeutic use) Mice Novobiocin (pharmacology, therapeutic use) Structure-Activity Relationship Treatment Outcome Trypanosoma brucei brucei (drug effects, enzymology) Trypanosomiasis, African (drug therapy)

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