James M. MurithiCécile PascalJade BathXavier BoulencNina F. GnädigCharisse Flerida A. PasajeKelly RubianoTomas YeoSachel MokSylvie KlieberPaul DesertMaría Belén Jiménez-DíazJutta MarfurtMélanie RouillierMohammed H. Cherkaoui-RbatiNathalie GobeauSergio WittlinAnne Catrin UhlemannRic N. PriceGrennady WirjanataRintis NoviyantiPatrick TumwebazeRoland A. CooperPhilip J. RosenthalLaura M. SanzFrancisco Javier GamoJayan JosephShivendra SinghSridevi BashyamJean Michel AugereauElie GiraudTanguy BozecThierry VermatGilles TuffalJean Michel GuillonJérôme MenegottoLaurent SalléGuillaume LouitMarie José CabanisMarie Françoise NicolasMichel DoubovetzkyRita MerinoNadir BessilaIñigo Angulo-BarturenDelphine BaudLidiya BebrevskaFanny EscudiéJacquin C. NilesBenjamin BlascoSimon CampbellGilles CourtemancheLaurent FraisseAlain PelletDavid A. FidockDidier LeroyFaculty of Tropical Medicine, Mahidol UniversitySyngene International LtdInfectious Diseases Research CollaborationBioaster, FranceDominican University of CaliforniaEijkman Institute for Molecular BiologySanofi Pasteur SAColumbia University Irving Medical CenterMenzies School of Health ResearchUniversity of California, San FranciscoUniversitat BaselSwiss Tropical and Public Health Institute (Swiss TPH)Massachusetts Institute of TechnologySanofi S.A.Nuffield Department of MedicineThe Art of DiscoveryTres Cantos2022-08-042022-08-042021-07-21Science Translational Medicine. Vol.13, No.603 (2021)19466242194662342-s2.0-85112546003https://repository.li.mahidol.ac.th/handle/20.500.14594/78027The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria.Mahidol UniversityMedicineArticleSCOPUS10.1126/scitranslmed.abg6013