biostudies-literatureEdgar RCSDHAC | National Health and Medical Research CouncilTherapeutic Innovation Australia (TIA)Therapeutic Innovation AustraliaDHAC | National Health and Medical Research Council (NHMRC)e0096624https://www.ebi.ac.uk/biostudies/studies/S-EPMC11237774biostudies-literatureUnknown15(6)To combat the global burden of malaria, development of new drugs to replace or complement current therapies is urgently required. Here, we show that the compound <b>MMV1557817</b> is a selective, nanomolar inhibitor of both <i>Plasmodium falciparum</i> and <i>Plasmodium vivax</i> aminopeptidases M1 and M17, leading to inhibition of end-stage hemoglobin digestion in asexual parasites. <b>MMV1557817</b> can kill sexual-stage <i>P. falciparum</i>, is active against murine malaria, and does not show any shift in activity against a panel of parasites resistant to other antimalarials. <b>MMV1557817</b>-resistant <i>P. falciparum</i> exhibited a slow growth rate that was quickly outcompeted by wild-type parasites and were sensitized to the current clinical drug, artemisinin. Overall, these resultmBioOn-target, dual aminopeptidase inhibition provides cross-species antimalarial activity.PMC11237774113630011853541150359Price RNSuraweera CDMalcolm TRAvery VMCreek DJde Koning-Ward TFGiannangelo CDuffy SDrinkwater NCounihan NADaware KCharman SAChowdhury MNoviyanti RMcGowan SWirjanata GScammells PJWittlin SSiddiqui GMarfurt JDans MChallis MEdgar RCSfalseOn-target, dual aminopeptidase inhibition provides cross-species antimalarial activity.To combat the global burden of malaria, development of new drugs to replace or complement current therapies is urgently required. Here, we show that the compound <b>MMV1557817</b> is a selective, nanomolar inhibitor of both <i>Plasmodium falciparum</i> and <i>Plasmodium vivax</i> aminopeptidases M1 and M17, leading to inhibition of end-stage hemoglobin digestion in asexual parasites. <b>MMV1557817</b> can kill sexual-stage <i>P. falciparum</i>, is active against murine malaria, and does not show any shift in activity against a panel of parasites resistant to other antimalarials. <b>MMV1557817</b>-resistant <i>P. falciparum</i> exhibited a slow growth rate that was quickly outcompeted by wild-type parasites and were sensitized to the current clinical drug, artemisinin. Overall, these result2024-01-01T00:00:00Z2024 Jun2026-04-29T12:04:37.208Z2025-04-05T15:47:20.051ZS-EPMC112377743871714110.1128/mbio.00966-24