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J Biol Chem. 2011 Aug 19;286(33):28940-7. doi: 10.1074/jbc.M111.268946. Epub 2011 Jun 25.

PG12, a phospholipid analog with potent antimalarial activity, inhibits Plasmodium falciparum CTP:phosphocholine cytidylyltransferase activity.

Author information

1
Research Unit on BioActive Molecules, Departament de Química Biomèdica, Instituto de Química Avanzada de Cataluña IQAC, CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain.

Abstract

In the human malaria parasite Plasmodium falciparum, the synthesis of the major and essential membrane phospholipid, phosphatidylcholine, occurs via the CDP-choline and the serine decarboxylase phosphoethanolamine methylation (SDPM) pathways, which are fueled by host choline, serine, and fatty acids. Both pathways share the final two steps catalyzed by two essential enzymes, P. falciparum CTP:phosphocholine cytidylyltransferase (PfCCT) and choline-phosphate transferase (PfCEPT). We identified a novel class of phospholipid mimetics, which inhibit the growth of P. falciparum as well as Leishmania and Trypanosoma species. Metabolic analyses showed that one of these compounds, PG12, specifically blocks phosphatidylcholine biosynthesis from both the CDP-choline and SDPM pathways via inhibition of PfCCT. In vitro studies using recombinant PfCCT showed a dose-dependent inhibition of the enzyme by PG12. The potent antimalarial of this compound, its low cytotoxicity profile, and its established mode of action make it an excellent lead to advance for further drug development and efficacy in vivo.

PMID:
21705805
PMCID:
PMC3190701
DOI:
10.1074/jbc.M111.268946
[Indexed for MEDLINE]
Free PMC Article

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