biostudies-literatureMurithi JMNational Institute of Allergy and Infectious DiseasesMedicines for Malaria VentureHuman Frontier Science ProgramNIAID NIH HHSNIEHS NIH HHSU.S. Department of DefenseBill and Melinda Gates FoundationWellcome Trusteabg6013https://www.ebi.ac.uk/biostudies/studies/S-EPMC8530196biostudies-literatureUnknown13(603)The emergence and spread of <i>Plasmodium falciparum</i> 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 <i>P. falciparum</i> 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 traffickiScience translational medicineThe antimalarial MMV688533 provides potential for single-dose cures with a high barrier to <i>Plasmodium falciparum</i> parasite resistance.PMC8530196AI109023R01 AI124678W81XWH-19-1-0086R01 AI109023OPP1201387LT000976/2016-L200909R01 AI139179T32 ES007020Desert PNiles JCMenegotto JAugereau JMJimenez-Diaz MBGobeau NGuillon JMNicolas MFDoubovetzky MSingh SCherkaoui-Rbati MHEscudie FBlasco BTumwebaze PPrice RNLouit GYeo TKlieber SCourtemanche GLeroy DMok SRouillier MMerino RBebrevska LWirjanata GFraisse LBessila NAngulo-Barturen IBoulenc XVermat TGnadig NFPellet ATuffal GFidock DAUhlemann ACRubiano KBath JGiraud EBozec TSanz LMBashyam SPascal CWittlin SMarfurt JGamo FJMurithi JMCabanis MJCampbell SSalle LNoviyanti RJoseph JCooper RAPasaje CFARosenthal PJBaud DfalseThe antimalarial MMV688533 provides potential for single-dose cures with a high barrier to <i>Plasmodium falciparum</i> parasite resistance.The emergence and spread of <i>Plasmodium falciparum</i> 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 <i>P. falciparum</i> 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 trafficki2021-01-01T00:00:00Z2021 Jul2025-04-22T09:19:22.616Z2025-04-05T22:59:01.783ZS-EPMC85301963429005810.1126/scitranslmed.abg6013