Targeting Plasmodium PI(4)K to eliminate malaria.

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Journal:
Nature, Volume: 504, Issue: 7479
Published:
December 12, 2013
PMID:
24284631
Authors:
Case W McNamara CW, Marcus Cs Lee MC, Chek Shik Lim CS, Siau Hoi Lim SH, Jason Roland J, Oliver Simon O, Bryan Ks Yeung BK, Arnab K Chatterjee AK, Susan L McCormack SL, Micah J Manary MJ, Anne-Marie Zeeman AM, Koen J Dechering KJ, Tr Santha Kumar TS, Philipp P Henrich PP, Kerstin Gagaring K, Maureen Ibanez M, Nobutaka Kato N, Kelli L Kuhen KL, Christoph Fischli C, Advait Nagle A, Matthias Rottmann M, David M Plouffe DM, Badry Bursulaya B, Stephan Meister S, Lucia Rameh L, Joerg Trappe J, Dorothea Haasen D, Martijn Timmerman M, Robert W Sauerwein RW, Rossarin Suwanarusk R, Bruce Russell B, Laurent Renia L, Francois Nosten F, David C Tully DC, Clemens Hm Kocken CH, Richard J Glynne RJ, Christophe Bodenreider C, David A Fidock DA, Thierry T Diagana TT, Elizabeth A Winzeler EA
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.