Identification of Hsp90 Inhibitors with Anti-Plasmodium Activity

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.