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Genetic and chemical validation of Plasmodium falciparum aminopeptidase PfA-M17 as a drug target in the hemoglobin digestion pathway
journal contribution
posted on 2023-02-14, 03:45 authored by RCS Edgar, G Siddiqui, K Hjerrild, TR Malcolm, NB Vinh, CT Webb, C Holmes, CA Macraild, HC Chernih, WW Suen, Natalie CounihanNatalie Counihan, DJ Creek, PJ Scammells, S McGowan, Tania De Koning-WardTania De Koning-WardPlasmodium 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.
History
Journal
eLifeVolume
11Article number
ARTN e80813Location
EnglandPublisher DOI
ISSN
2050-084XeISSN
2050-084XLanguage
EnglishPublication classification
C1 Refereed article in a scholarly journalPublisher
eLIFE SCIENCES PUBL LTDUsage metrics
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Keywords
Science & TechnologyLife Sciences & BiomedicineBiologyLife Sciences & Biomedicine - Other TopicsPfalciparumhemoglobin digestionaminopeptidasedrug targetMALARIA PARASITESINHIBITIONM1BIOSYNTHESISDEGRADATIONBESTATINPROTEINSSTRATEGYREVEALSP. falciparuminfectious diseasemicrobiologyAminopeptidasesDigestionHemoglobinsHumansMalaria, FalciparumPlasmodium falciparumProtease InhibitorsProtozoan ProteinsBiotechnologyVector-Borne DiseasesInfectious DiseasesOrphan DrugMalariaRare Diseases5.1 Pharmaceuticals5 Development of treatments and therapeutic interventionsInfection3 Good Health and Well Being