Yevgeniya Antonova-KochStephan MeisterMatthew AbrahamMadeline R. LuthSabine OttilieAmanda K. LukensTomoyo Sakata-KatoManu VanaerschotEdward OwenJuan Carlos Jado RodriguezSteven P. MaherJaeson CallaDavid PlouffeYang ZhongKaisheng ChenVictor ChaumeauAmy J. ConwayCase W. McNamaraMaureen IbanezKerstin GagaringFernando Neria SerranoKorina EribezCullin Mc Lean TaggardAndrea L. CheungChristie LincolnBiniam AmbachewMelanie RouillierDionicio SiegelFrançois NostenDennis E. KyleFrancisco Javier GamoYingyao ZhouManuel LlinásDavid A. FidockDyann F. WirthJeremy BurrowsBrice CampoElizabeth A. WinzelerGlaxoSmithKline plc, SpainHarvard School of Public HealthUniversity of California, San DiegoThe University of GeorgiaColumbia University Medical CenterUniversity of California, San Diego, School of MedicineMahidol UniversityThe Genomics Institute of the Novartis Research FoundationNuffield Department of Clinical MedicineUniversity of South Florida, TampaPennsylvania State UniversityBroad InstituteBioSeroCalifornia Institute for Biomedical ResearchMedicines for Malaria Venture2019-08-282019-08-282018-12-07Science. Vol.362, No.6419 (2018)10959203003680752-s2.0-85057744039https://repository.li.mahidol.ac.th/handle/20.500.14594/47459© 2017 The Authors, some rights reserved To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action.Mahidol UniversityMultidisciplinaryArticleSCOPUS10.1126/science.aat9446