Case W. McNamaraMarcus C.S. LeeChek Shik LimSiau Hoi LimJason RolandAdvait NagleOliver SimonBryan K.S. YeungArnab K. ChatterjeeSusan L. McCormackMicah J. ManaryAnne Marie ZeemanKoen J. DecheringT. R.Santha KumarPhilipp P. HenrichKerstin GagaringMaureen IbanezNobutaka KatoKelli L. KuhenChristoph FischliMatthias RottmannDavid M. PlouffeBadry BursulayaStephan MeisterLucia RamehJoerg TrappeDorothea HaasenMartijn TimmermanRobert W. SauerweinRossarin SuwanaruskBruce RussellLaurent ReniaFrancois NostenDavid C. TullyClemens H.M. KockenRichard J. GlynneChristophe BodenreiderDavid A. FidockThierry T. DiaganaElizabeth A. WinzelerThe Genomics Institute of the Novartis Research FoundationColumbia University Medical CenterNovartis Institutes for Tropical DiseaseUniversity of California, San DiegoBiomedical Primate Research Centre - RijswijkTropIQ Health SciencesSwiss Tropical and Public Health Institute (Swiss TPH)Universitat BaselBoston University School of MedicineNovartis International AGRadboud University Nijmegen Medical CentreAgency for Science, Technology and Research, SingaporeYong Loo Lin School of MedicineNuffield Department of Clinical MedicineMahidol University2018-10-192018-10-192013-11-29Nature. Vol.504, No.7479 (2013), 248-25314764687002808362-s2.0-84890428942https://repository.li.mahidol.ac.th/handle/20.500.14594/32815Achieving 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.Mahidol UniversityMultidisciplinaryArticleSCOPUS10.1038/nature12782