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

Kirsten J. Meyer, Theresa A. Shapiro

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)489-499
Number of pages11
JournalJournal of Infectious Diseases
Volume208
Issue number3
DOIs
StatePublished - Aug 1 2013

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

Fingerprint Dive into the research topics of 'Potent antitrypanosomal activities of heat shock protein 90 inhibitors in vitro and in vivo'. Together they form a unique fingerprint.

Cite this