phosphatidylinositol-4-phosphate and Malaria

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.

Topics: 1-Phosphatidylinositol 4-Kinase; Adenosine Triphosphate; Animals; Binding Sites; Cytokinesis; Drug Resistance; Fatty Acids; Female; Hepatocytes; Humans; Imidazoles; Life Cycle Stages; Macaca mulatta; Malaria; Male; Models, Biological; Models, Molecular; Phosphatidylinositol Phosphates; Plasmodium; Pyrazoles; Quinoxalines; rab GTP-Binding Proteins; Reproducibility of Results; Schizonts