Heat Shock Protein 90 is Critical for Plasmodium Parasite Liver Stage Development

Abstract

Malaria remains a severe global health burden, and there is an urgent need to develop effective strategies to combat the Plasmodium parasites responsible for the disease. The molecular chaperone heat shock protein 90 (Hsp90) has emerged as an essential protein for blood stage Plasmodium parasites, but its role during malaria's elusive liver stages remain unclear. Studies on protein function throughout the infection are challenging as Hsp90 is highly conserved between the parasite and human host. To address this issue, we used target‐based screens to identify compounds that bind to Plasmodium (Pf) and human Hsp90 with varying species selectivity and used them as chemical probes. All identified Hsp90‐binding compounds were potent blood and liver stage Plasmodium inhibitors in cell‐based malaria assays. Importantly, Hsp90 inhibitors synergistically reduced liver stage parasite viability when used in combination with phosphatidylinositol 3‐kinase inhibitors. Most notably, liver stage parasite inhibition strongly correlated with binding to PfHsp90, but not the human host protein. Analysis of Hsp90 protein and gene expression throughout the liver stage coupled with time course inhibition studies further support a critical role of Plasmodium Hsp90 in early liver stage parasite development. Our results suggest that PfHsp90, but not human Hsp90, is essential to malaria's liver stage and highlight the potential to selectively inhibit PfHsp90 in combination therapies for malaria treatment and prevention.Support or Funding InformationThis work was supported by the NIH for laboratory support (GM099796 to E.R.D.) and the Duke Pharmacological Sciences Training Program for fellowship support (2T32GM007105‐41 to A.I.K.).