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Here, we show that the compound\n                      <jats:bold>MMV1557817<\/jats:bold>\n                      is a selective, nanomolar inhibitor of both\n                      <jats:italic>Plasmodium falciparum<\/jats:italic>\n                      and\n                      <jats:italic>Plasmodium vivax<\/jats:italic>\n                      aminopeptidases M1 and M17, leading to inhibition of end-stage hemoglobin digestion in asexual parasites.\n                      <jats:bold>MMV1557817<\/jats:bold>\n                      can kill sexual-stage\n                      <jats:italic>P. falciparum<\/jats:italic>\n                      , is active against murine malaria, and does not show any shift in activity against a panel of parasites resistant to other antimalarials.\n                      <jats:bold>MMV1557817<\/jats:bold>\n                      -resistant\n                      <jats:italic>P. falciparum<\/jats:italic>\n                      exhibited a slow growth rate that was quickly outcompeted by wild-type parasites and were sensitized to the current clinical drug, artemisinin. Overall, these results confirm\n                      <jats:bold>MMV1557817<\/jats:bold>\n                      as a lead compound for further drug development and highlights the potential of dual inhibition of M1 and M17 as an effective multi-species drug-targeting strategy.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Each year, malaria infects approximately 240 million people and causes over 600,000 deaths, mostly in children under 5 years of age. For the past decade, artemisinin-based combination therapies have been recommended by the World Health Organization as the standard malaria treatment worldwide. Their widespread use has led to the development of artemisinin resistance in the form of delayed parasite clearance, alongside the rise of partner drug resistance. There is an urgent need to develop and deploy new antimalarial agents with novel targets and mechanisms of action. Here, we report a new and potent antimalarial compound, known as\n                        <jats:bold>MMV1557817<\/jats:bold>\n                        , and show that it targets multiple stages of the malaria parasite lifecycle, is active in a preliminary mouse malaria model, and has a novel mechanism of action. Excitingly, resistance to\n                        <jats:bold>MMV15578117<\/jats:bold>\n                        appears to be self-limiting, suggesting that development of the compound may provide a new class of antimalarial.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00966-24","type":"journal-article","created":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T09:00:18Z","timestamp":1715158818000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["On-target, dual aminopeptidase inhibition provides cross-species antimalarial activity"],"prefix":"10.1128","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5974-8625","authenticated-orcid":false,"given":"Rebecca C. 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D Giannangelo C Challis M Siddiqui G Edgar R Malcolm T Webb C Drinkwater N Vinh N MacRaild C Counihan N Duffy S Wittlin S Devine S Avery V de Koning-Ward T Scammells P McGowan S. 2023. Chemoproteomics validates selective targeting of Plasmodium M1 alanyl aminopeptidase as a cross-species strategy to treat malaria. 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