Journal Article

Targeting Plasmodium PI(4)K to eliminate malaria

Kocken, Clemens H. M., Trappe, Joerg, Simon, Oliver, Plouffe, David M., Roland, Jason, Bodenreider, Christophe, Dechering, Koen J., Fidock, David A., Kuhen, Kelli L., Winzeler, Elizabeth A., Chatterjee, Arnab K., Bursulaya, Badry, Lim, Siau Hoi, Diagana, Thierry T., Kato, Nobutaka, McNamara, Case W., Rameh, Lucia, Suwanarusk, Rossarin, Henrich, Philipp P., Nagle, Advait, Meister, Stephan, Russell, Bruce, McCormack, Susan L., Lim, Chek Shik, Fischli, Christoph, Ibanez, Maureen, Manary, Micah J., Gagaring, Kerstin, Yeung, Bryan K. S., Lee, Marcus C. S., Zeeman, Anne-Marie, Rottmann, Matthias, Renia, Laurent, Haasen, Dorothea, Glynne, Richard J., Nosten, Francois, Kumar, T. R. Santha, Timmerman, Martijn, Sauerwein, Robert W., Tully, David C.

2013

Overview

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. The lipid kinase phosphatidylinositol-4-OH kinase (PI(4)K) is identified as a target of the imidazopyrazines, a new antimalarial compound class that can inhibit several Plasmodium species at each stage of the parasite life cycle; the imidazopyrazines exert their inhibitory action by interacting with the ATP-binding pocket of PI(4)K. A multifunction target for antimalarials To eliminate malaria completely it is necessary to cure an individual of all stages in the malaria parasite's life cycle including the symptomatic blood-stage infection and the preceding liver-stage infection (to prevent relapse) and also to block transmission to mosquitoes. Here Elizabeth Winzeler and colleagues identify phosphatidylinositol-4-OH kinase (PI(4)K) as a potential drug target that is essential to fatty acid metabolism in all stages of the Plasmodium parasite. The authors show that a family of compounds with an imidazopyrazine core, distinct from known antimalarials, inhibits PI(4)K and also inhibits the development of multiple Plasmodium species at each stage of the life cycle. Their analyses reveal that the imidazopyrazines interact with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4 phosphate and interfering with cell division.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 1-Phosphatidylinositol 4-Kinase - antagonists & inhibitors / 1-Phosphatidylinositol 4-Kinase - chemistry / 1-Phosphatidylinositol 4-Kinase - genetics / 1-Phosphatidylinositol 4-Kinase - metabolism / 13/106 / 13/109 / 14/35 / 14/63 / 45/23 / 45/61 / 59/5 / 631/154/556 / 631/326/417/1716 / 631/92/93 / 692/699/255/1629 / 82/80 / 82/83 / Adenosine Triphosphate - metabolism / Animals / Binding Sites / Cytokinesis - drug effects / Drug dosages / Drug Resistance - drug effects / Drug Resistance - genetics / Fatty Acids - metabolism / Female / Hepatocytes - parasitology / Humanities and Social Sciences / Humans / Imidazoles - metabolism / Imidazoles - pharmacology / Infections / Kinases / Licenses / Life Cycle Stages - drug effects / Macaca mulatta / Malaria / Malaria - drug therapy / Malaria - parasitology / Male / Models, Biological / Models, Molecular / Mosquitoes / multidisciplinary / Parasites / Phosphatidylinositol Phosphates - metabolism / Plasma / Plasmodium / Plasmodium - classification / Plasmodium - drug effects / Plasmodium - enzymology / Plasmodium - growth & development / Plasmodium falciparum / Pyrazoles - metabolism / Pyrazoles - pharmacology / Quinoxalines - metabolism / Quinoxalines - pharmacology / rab GTP-Binding Proteins - genetics / rab GTP-Binding Proteins - metabolism / Reproducibility of Results / Schizonts - cytology / Schizonts - drug effects / Science / Vector-borne diseases