title: PG12, a phospholipid analog with potent antimalarial activity, inhibits Plasmodium falciparum CTP:phosphocholine cytidylyltransferase activity.
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.
authors.affiliation: Research Unit on BioActive Molecules (RUBAM), Departament de Química Biomèdica, Instituto de Química Avanzada de Cataluña IQAC, CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: González-Bulnes
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, and.
authors.forename: April M
authors.initials: AM
authors.lastname: Bobenchik
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, and.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Augagneur
authors.affiliation: Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Universite Montpellier II, 34095 Montpellier, France.
authors.forename: Rachel
authors.initials: R
authors.lastname: Cerdan
authors.affiliation: Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Universite Montpellier II, 34095 Montpellier, France.
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Vial
authors.affiliation: Research Unit on BioActive Molecules (RUBAM), Departament de Química Biomèdica, Instituto de Química Avanzada de Cataluña IQAC, CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain,. Electronic address: alsqob@cid.csic.es.
authors.forename: Amadeu
authors.initials: A
authors.lastname: Llebaria
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, and. Electronic address: Choukri.benmamoun@yale.edu.
authors.forename: Choukri
authors.initials: C
authors.lastname: Ben Mamoun
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology*; D019916:Choline-Phosphate Cytidylyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000201:enzymology; D010743:Phospholipids / Q000737:chemistry / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000201:enzymology*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D010743:Phospholipids; D015800:Protozoan Proteins; D019916:Choline-Phosphate Cytidylyltransferase