Journal
NATURE
Volume 504, Issue 7479, Pages 248-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature12782
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Funding
- Wellcome Trust [WT078285, WT096157]
- Medicines for Malaria Venture (MMV)
- Swiss Tropical and Public Health Institute
- Columbia University
- Novartis Institute for Tropical Diseases
- Singapore Immunology Network and Horizontal Programme on Infectious Diseases under the Agency Science Technology and Research (A*STAR, Singapore)
- Wellcome Trust (UK)
- Wellcome Trust (UK), as part of the Oxford Tropical Medicine Research Programme of Wellcome Trust-Mahidol University
- Bill and Melinda Gates Foundation
- National Institutes of Health [R01AI090141, R01085584, R01079709]
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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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