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Targeting Plasmodium PI(4)K to eliminate malaria.

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

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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