Targeting Plasmodium PI(4)K to eliminate malaria
Top Cited Papers
Open Access
- 27 November 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 504 (7479), 248-253
- https://doi.org/10.1038/nature12782
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.Keywords
This publication has 48 references indexed in Scilit:
- Imaging of Plasmodium Liver Stages to Drive Next-Generation Antimalarial Drug DiscoveryScience, 2011
- Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blueProceedings of the National Academy of Sciences, 2011
- Spiroindolones, a Potent Compound Class for the Treatment of MalariaScience, 2010
- Isolation of viable Plasmodium falciparum merozoites to define erythrocyte invasion events and advance vaccine and drug developmentProceedings of the National Academy of Sciences, 2010
- A Plant-Like Kinase in Plasmodium falciparum Regulates Parasite Egress from ErythrocytesScience, 2010
- Dual roles for the Drosophila PI 4-kinase Four wheel drive in localizing Rab11 during cytokinesisThe Journal of cell biology, 2009
- In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screenProceedings of the National Academy of Sciences, 2008
- Heritable targeted gene disruption in zebrafish using designed zinc-finger nucleasesNature Biotechnology, 2008
- Plasmodium Food Vacuole Plasmepsins Are Activated by FalcipainsJournal of Biological Chemistry, 2008
- Efficient site-specific integration in Plasmodium falciparum chromosomes mediated by mycobacteriophage Bxb1 integraseNature Methods, 2006