title: Plasmodium falciparum: stage specific effects of a selective inhibitor of lactate dehydrogenase.
abstract: Plasmodium falciparum lactate dehydrogenase (PfLDH) is essential for ATP generation. Based on structural differences within the active site between P. falciparum and human LDH, we have identified a series of heterocyclic azole-based inhibitors that selectively bind within the PfLDH but not the human LDH (hLDH) active site and showed anti-malarial activity in vitro and in vivo. Here we expand on an azole, OXD1, from this series and found that the anti-P. falciparum activity was retained against a panel of strains independently of their anti-malarial drug sensitivity profile. Trophozoites had relatively higher PfLDH enzyme activity and PfLDH-RNA expression levels than rings and were the most susceptible stages to OXD1 exposure. This is probably linked to their increased energy requirements and consistent with glycolysis being an essential metabolic pathway for parasite survival within the erythrocyte. Further structural elaboration of these azoles could lead to the identification of compounds that target P. falciparum through such a novel mechanism and with more potent anti-malarial activity.
authors.affiliation: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK. livia.vivas@lshtm.ac.uk
authors.forename: Livia
authors.initials: L
authors.lastname: Vivas
authors.forename: Anna
authors.initials: A
authors.lastname: Easton
authors.forename: Howard
authors.initials: H
authors.lastname: Kendrick
authors.forename: Angus
authors.initials: A
authors.lastname: Cameron
authors.forename: Jose-Luis
authors.initials: JL
authors.lastname: Lavandera
authors.forename: David
authors.initials: D
authors.lastname: Barros
authors.forename: Federico Gomez
authors.initials: FG
authors.lastname: de las Heras
authors.forename: R Leo
authors.initials: RL
authors.lastname: Brady
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D018613:Microscopy, Confocal; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D010617:Phenanthridines / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development; D016053:RNA, Protozoan / Q000096:biosynthesis; D013045:Species Specificity
chemical_list: C504849:4-hydroxy-1,2,5-oxadiazole-3-carboxylic acid; D000962:Antimalarials; D002264:Carboxylic Acids; D005456:Fluorescent Dyes; D010069:Oxadiazoles; D010617:Phenanthridines; D016053:RNA, Protozoan; C058428:hydroethidine; D007770:L-Lactate Dehydrogenase