Targeting Plasmodium PI(4)K to eliminate malaria.
McNamara, Case W. 1, *; Lee, Marcus C. S. 2, *; Lim, Chek Shik 3; Lim, Siau Hoi 3; Roland, Jason 1; Nagle, Advait 1; Simon, Oliver 3; Yeung, Bryan K. S. 3; Chatterjee, Arnab K. 1; McCormack, Susan L. 1; Manary, Micah J. 4; Zeeman, Anne-Marie 5; Dechering, Koen J. 6; SanthaKumar, T. R. 2; Henrich, Philipp P. 2; Gagaring, Kerstin 1; Ibanez, Maureen 1; Kato, Nobutaka 1; Kuhen, Kelli L. 1; Fischli, Christoph 7; Rottmann, Matthias 7, 8; Plouffe, David M. 1; Bursulaya, Badry 1; Meister, Stephan 4; Rameh, Lucia 9; Trappe, Joerg 10; Haasen, Dorothea 10; Timmerman, Martijn 6; Sauerwein, Robert W. 6, 11; Suwanarusk, Rossarin 12; Russell, Bruce 12, 13; Renia, Laurent 12; Nosten, Francois 14, 15; Tully, David C. 1; Kocken, Clemens H. M. 5; Glynne, Richard J. 1; Bodenreider, Christophe 3; Fidock, David A. 2, 16; Diagana, Thierry T. 3; Winzeler, Elizabeth A. 1, 4
[Article]
Nature.
504(7479):248-266, December 12, 2013.
(Format: HTML, PDF)
: 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.
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