TY - JOUR TI - Genetic and chemical validation of Plasmodium falciparum aminopeptidase PfA-M17 as a drug target in the hemoglobin digestion pathway AU - Edgar, Rebecca CS AU - Siddiqui, Ghizal AU - Hjerrild, Katheryn AU - Malcolm, Tess R AU - Vinh, Natalie B AU - Webb, Chaille T AU - Holmes, Clare AU - MacRaild, Christopher A AU - Chernih, Hope C AU - Suen, Willy W AU - Counihan, Natalie A AU - Creek, Darren J AU - Scammells, Peter J AU - McGowan, Sheena AU - de Koning-Ward, Tania F A2 - Soldati-Favre, Dominique A2 - Blackman, Michael J VL - 11 PY - 2022 DA - 2022/09/13 SP - e80813 C1 - eLife 2022;11:e80813 DO - 10.7554/eLife.80813 UR - https://doi.org/10.7554/eLife.80813 AB - Plasmodium falciparum, the causative agent of malaria, remains a global health threat as parasites continue to develop resistance to antimalarial drugs used throughout the world. Accordingly, drugs with novel modes of action are desperately required to combat malaria. P. falciparum parasites infect human red blood cells where they digest the host’s main protein constituent, hemoglobin. Leucine aminopeptidase PfA-M17 is one of several aminopeptidases that have been implicated in the last step of this digestive pathway. Here, we use both reverse genetics and a compound specifically designed to inhibit the activity of PfA-M17 to show that PfA-M17 is essential for P. falciparum survival as it provides parasites with free amino acids for growth, many of which are highly likely to originate from hemoglobin. We further show that loss of PfA-M17 results in parasites exhibiting multiple digestive vacuoles at the trophozoite stage. In contrast to other hemoglobin-degrading proteases that have overlapping redundant functions, we validate PfA-M17 as a potential novel drug target. KW - P. falciparum KW - hemoglobin digestion KW - aminopeptidase KW - drug target JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -