Identification of Hsp90 inhibitors with anti-Plasmodium activity [PublishAheadOfPrint]

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 synergistically reduces liver stage parasite load in combination with the phosphatidylinositol 3-kinase inhibitor PIK-75. 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 to develop species selective PfHsp90 inhibitors that could act synergistically in combination therapies to prevent and treat malaria.

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