1. Academic Validation
  2. Identification of Hsp90 Inhibitors with Anti-Plasmodium Activity

Identification of Hsp90 Inhibitors with Anti-Plasmodium Activity

  • Antimicrob Agents Chemother. 2018 Mar 27;62(4):e01799-17. doi: 10.1128/AAC.01799-17.
Dora Posfai 1 Amber L Eubanks 2 Allison I Keim 2 Kuan-Yi Lu 1 Grace Z Wang 2 Philip F Hughes 3 Nobutaka Kato 4 Timothy A Haystead 3 Emily R Derbyshire 5 2
Affiliations

Affiliations

  • 1 Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA.
  • 2 Department of Chemistry, Duke University, Durham, North Carolina, USA.
  • 3 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
  • 4 The Broad Institute, Cambridge, Massachusetts, USA.
  • 5 Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, USA emily.derbyshire@duke.edu.
Abstract

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.

Keywords

Hsp90; Plasmodium; host-pathogen interaction; malaria.

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