Plasmodium falciparum Choline Kinase Inhibition Leads to a Major Decrease in Phosphatidylethanolamine Causing Parasite Death.
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.
Department of Pharmaceutical and Organic Chemistry, c/ Campus de Cartuja, Faculty of Pharmacy, University of Granada, Granada, Spain.
Lucía
L
Serrán-Aguilera
Biomedical Sciences Research Complex, University of St Andrews, North Haugh, St Andrews, Fife, United Kingdom.
Helen
H
Denton
Department of Pharmaceutical and Organic Chemistry, c/ Campus de Cartuja, Faculty of Pharmacy, University of Granada, Granada, Spain.
Belén
B
Rubio-Ruiz
ISGlobal, Barcelona Centre for International Health Research (CRESIB), Hospital Clínic - University of Barcelona Barcelona, Spain.
Borja
B
López-Gutiérrez
Department of Pharmaceutical and Organic Chemistry, c/ Campus de Cartuja, Faculty of Pharmacy, University of Granada, Granada, Spain.
Antonio
A
Entrena
ISGlobal, Barcelona Centre for International Health Research (CRESIB), Hospital Clínic - University of Barcelona Barcelona, Spain.
Luis
L
Izquierdo
Biomedical Sciences Research Complex, University of St Andrews, North Haugh, St Andrews, Fife, United Kingdom.
Terry K
TK
Smith
Department of Pharmaceutical and Organic Chemistry, c/ Campus de Cartuja, Faculty of Pharmacy, University of Granada, Granada, Spain.|Biosanitary Institute of Granada (ibs.GRANADA), SAS-Universidad de Granada, Granada, Spain.
Ana
A
Conejo-García
BIFI, University of Zaragoza, BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n, Campus Rio Ebro, Zaragoza, Spain.|Fundación ARAID, Zaragoza, Spain.
Ramon
R
Hurtado-Guerrero
D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D002478:Cells, Cultured; D002797:Choline Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008958:Models, Molecular; D010714:Phosphatidylethanolamines / Q000096:biosynthesis*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D053058:Trophozoites / Q000187:drug effects / Q000201:enzymology
D000962:Antimalarials; D010714:Phosphatidylethanolamines; D015800:Protozoan Proteins; C483858:phosphatidylethanolamine; D002797:Choline Kinase