Abstract
Malaria is a life-threatening disease caused by different species of the protozoan parasite Plasmodium, with P. falciparum being the deadliest. Increasing parasitic resistance to existing antimalarials makes the necessity of novel avenues to treat this disease an urgent priority. The enzymes responsible for the synthesis of phosphatidylcholine and phosphatidylethanolamine are attractive drug targets to treat malaria as their selective inhibition leads to an arrest of the parasite’s growth and cures malaria in a mouse model. We present here a detailed study that reveals a mode of action for two P. falciparum choline kinase inhibitors both in vitro and in vivo. The compounds present distinct binding modes to the choline/ethanolamine-binding site of P. falciparum choline kinase, reflecting different types of inhibition. Strikingly, these compounds primarily inhibit the ethanolamine kinase activity of the P. falciparum choline kinase, leading to a severe decrease in the phosphatidylethanolamine levels within P. falciparum, which explains the resulting growth phenotype and the parasites death. These studies provide an understanding of the mode of action, and act as a springboard for continued antimalarial development efforts selectively targeting P. falciparum choline kinase.
Highlights
Malaria remains an important global health concern
As it was highly likely that treatment of either BR23 or BR25 to the whole parasite could affect phospholipid biosynthesis, namely the synthesis of PC and PE, we performed lipidomic analysis of parasites treated with the compounds and compared these to untreated
It has been suggested that P. falciparum has separate enzymes catalysing phophorylation of Cho and Etn[30,31], these authors state that redundancy remains a possibility
Summary
Malaria remains an important global health concern. According to the latest estimates, 214 million cases of malaria occurred globally in 2014 and approximately half million deaths, primarily children aged under 5 year, in Africa[1]. The synthesis is initiated by phosphorylation of Cho and Etn to render phosphocholine (PCho) and phosphoethanolamine (PEtn) by choline kinase (CK) and ethanolamine kinase (EK) respectively. We have shown recently that compound BR33 (Figure S1) was able to induce local conformational changes in the Cho-binding site, which induced the aperture of an adjacent binding site[22]. Considering their inhibition properties in the human CKα1 (HsCKα1) and the high identity between the human CKα1 and the P. falciparum CK (PfCK) at the binding site The two most active compounds, BR23 and BR25 (Figure S1), with IC50 of 3 and 2 nM respectively[24], were selected to further investigate their mode of action against P. falciparum
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