Identification of Hsp90 Inhibitors with Anti-Plasmodium Activity.

Published online

Journal Article

Malaria remains a global health burden partly due to Plasmodium parasite resistance to first-line therapeutics. The molecular chaperone heat shock protein 90 (Hsp90) has emerged as an essential protein for blood-stage Plasmodium parasites, but details about its function during malaria's elusive liver stage are unclear. We used target-based screens to identify compounds that bind to Plasmodium falciparum and human Hsp90, which revealed insights into chemotypes with species-selective binding. Using cell-based malaria assays, we demonstrate that all identified Hsp90-binding compounds are liver- and blood-stage Plasmodium inhibitors. Additionally, the Hsp90 inhibitor SNX-0723 in combination with the phosphatidylinositol 3-kinase inhibitor PIK-75 synergistically reduces the liver-stage parasite load. Time course inhibition studies with the Hsp90 inhibitors and expression analysis support a role for Plasmodium Hsp90 in late-liver-stage parasite development. Our results suggest that Plasmodium Hsp90 is essential to liver- and blood-stage parasite infections and highlight an attractive route for development of species-selective PfHsp90 inhibitors that may act synergistically in combination therapies to prevent and treat malaria.

Full Text

Duke Authors

Cited Authors

  • Posfai, D; Eubanks, AL; Keim, AI; Lu, K-Y; Wang, GZ; Hughes, PF; Kato, N; Haystead, TA; Derbyshire, ER

Published Date

  • April 2018

Published In

Volume / Issue

  • 62 / 4

PubMed ID

  • 29339390

Pubmed Central ID

  • 29339390

Electronic International Standard Serial Number (EISSN)

  • 1098-6596

Digital Object Identifier (DOI)

  • 10.1128/AAC.01799-17

Language

  • eng

Conference Location

  • United States