Targeting Plasmodium PI(4)K to eliminate malaria
McNamara CW., Lee MCS., Lim CS., Lim SH., Roland J., Nagle A., Simon O., Yeung BKS., Chatterjee AK., McCormack SL., Manary MJ., Zeeman AM., Dechering KJ., Kumar TRS., Henrich PP., Gagaring K., Ibanez M., Kato N., Kuhen KL., Fischli C., Rottmann M., Plouffe DM., Bursulaya B., Meister S., Rameh L., Trappe J., Haasen D., Timmerman M., Sauerwein RW., Suwanarusk R., Russell B., Renia L., Nosten F., Tully DC., Kocken CHM., Glynne RJ., Bodenreider C., Fidock DA., Diagana TT., Winzeler EA.
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. © 2013 Macmillan Publishers Limited. All rights reserved.