Targeting Plasmodium PI(4)K to eliminate malaria.
McNamara CW., Lee MC., Lim CS., Lim SH., Roland J., Simon O., Yeung BK., Chatterjee AK., McCormack SL., Manary MJ., Zeeman A-M., Dechering KJ., Kumar TS., Henrich PP., Gagaring K., Ibanez M., Kato N., Kuhen KL., Fischli C., Nagle A., 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 CH., 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.