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J Infect Dis. 2013 Aug 1;208(3):489-99. doi: 10.1093/infdis/jit179. Epub 2013 Apr 22.

Potent antitrypanosomal activities of heat shock protein 90 inhibitors in vitro and in vivo.

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1
Department of Pharmacology and Molecular Sciences, The Johns Hopkins UniversitySchool of Medicine, Baltimore, MD, USA.

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.

KEYWORDS:

17-AAG; 17-DMAG; Hsp90; Trypanosoma brucei; cell cycle; drug; geldanamycin; human African trypanosomiasis; inhibitor; kinetoplast

PMID:
23630365
PMCID:
PMC3699005
DOI:
10.1093/infdis/jit179
[Indexed for MEDLINE]
Free PMC Article
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