Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
9442758 | Experimental Parasitology | 2005 | 10 Pages |
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.
Keywords
URBCiRBCRBCAPADGAPDHIC50fifty percent inhibitory concentrationPBSRed blood cellsDNAAdenosine TriphosphateATPdeoxyribonucleic acidRNAribonucleic acidInhibitionProtozoaStage specificityphosphate buffer salinelactate dehydrogenaseNADnicotinamide adenine dinucleotidepolymerase chain reactionPCRPlasmodium falciparumPlasmodium falciparum lactate dehydrogenaseinfected red blood cellsglyceraldehyde-3-phosphate dehydrogenase
Related Topics
Life Sciences
Immunology and Microbiology
Parasitology
Authors
Livia Vivas, Anna Easton, Howard Kendrick, Angus Cameron, Jose-Luis Lavandera, David Barros, Federico Gomez de las Heras, R. Leo Brady, Simon L. Croft,