Journal Article

Targeting Plasmodium phosphatidylinositol 4-kinase to eliminate malaria

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

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-kinase (PI4K), as the target of imidazopyrazines, a novel 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 PI4K, altering the intracellular distribution of phosphatidylinositol 4-phosphate. Collectively, our data define PI4K 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.