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Identification of Hsp90 Inhibitors with Anti-Plasmodium Activity.

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.

SUBMITTER: Posfai D

PROVIDER: S-EPMC5913967 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Identification of Hsp90 Inhibitors with Anti-Plasmodium Activity.

Posfai Dora D Eubanks Amber L AL Keim Allison I AI Lu Kuan-Yi KY Wang Grace Z GZ Hughes Philip F PF Kato Nobutaka N Haystead Timothy A TA Derbyshire Emily R ER

Antimicrobial agents and chemotherapy 20180327 4

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-se ...[more]

PMID: 29339390

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Project description:The recent reduction in mortality due to malaria is being threatened by the appearance of Plasmodium falciparum parasites that are resistant to artemisinin in Southeast Asia. To limit the impact of resistant parasites and their spread across the world, there is a need to validate anti-malarial drug targets and identify new leads that will serve as foundations for future drug development programmes targeting malaria. Towards that end, the antiplasmodial potential of several Hsp90 inhibitors was characterized. Because, the Hsp90 chaperone has been suggested as a good drug target against multiple parasitic infections including malaria.Chemically diverse sets of Hsp90 inhibitors, evaluated in clinical trials as anti-cancer agents, were tested against the malaria parasite. Most of the compounds showed strong antiplasmodial activity in growth inhibition assays against chloroquine sensitive and resistant strains. There was a good agreement between the compound in vitro anti-parasitic activity and their affinity against the Plasmodium chaperone. The two most potent Hsp90 inhibitors also showed cytocidal activity against two P. falciparum strains. Their antiplasmodial activity affected all parasite forms during the malaria blood cycle. However, the compounds activity against the parasite showed no synergy when combined with anti-malarial drugs, like chloroquine or DHA.The Hsp90 inhibitors anti-parasitic activity correlates with their affinity to their predicted target the P. falciparum chaperone Hsp90. However, the most effective compounds also showed high affinity for a close homologue, Grp94. This association points to a mode of action for Hsp90 inhibitors that correlate compound efficacy with multi-target engagement. Besides their ability to limit parasite replication, two compounds also significantly impacted P. falciparum viability in vitro. Finally, a structural analysis suggests that the best hit represents a promising scaffold to develop parasite specific leads according.The results shown that Hsp90 inhibitors are lethal against the malaria parasite. The correlation between biochemical and in vitro data strongly supports Hsp90 as a drug target against the malaria parasite. Furthermore, at least one Hsp90 inhibitor developed as anticancer therapeutics could serve as starting point to generate P. falciparum-specific lead compounds.

Dataset Information

Identification of Hsp90 Inhibitors with Anti-Plasmodium Activity.

Publications

Identification of Hsp90 Inhibitors with Anti-Plasmodium Activity.

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