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.

CTP:phosphocholine cytidylyltransferase: Function, regulation, and structure of an amphitropic enzyme required for membrane biogenesis

“…Alkyl phosphocholines such as edelfosine are the most well-studied inhibitors [189], and have been utilized widely to explore physiological functions for CCTs [114,131]. Cationic phospholipid analogs that inhibit CCT activity have been developed as potential anti-malarial drugs against Plasmodium falciparum [190]. This plasmodium requires its own CDP-choline derived PC for propagation in red blood cells, hence this pathway has become a good prospect for intervention in quinoline-resistant plasmodia [191].…”

Lipid synthesis in protozoan parasites: A comparison between kinetoplastids and apicomplexans

“…Recently, a phospholipid analog affecting P. falciparum development and intraerythrocytic maturation through inhibition of PC synthesis via blocking CTP-phosphocholine cytidylyltransferase has been described [318]. Treatment of parasitized erythrocytes with the novel compound, PG12, lead to strongly reduced PC synthesis using choline or ethanolamine as substrates, indicating that both the CDP-choline and the serine-decarboxylase phosphoethanolamine N-methyltransferase pathways are affected by PG12 [318].…”

“…Treatment of parasitized erythrocytes with the novel compound, PG12, lead to strongly reduced PC synthesis using choline or ethanolamine as substrates, indicating that both the CDP-choline and the serine-decarboxylase phosphoethanolamine N-methyltransferase pathways are affected by PG12 [318]. In a different study aimed at identifying inhibitors of P. falciparum phosphoethanolamine N-methyltransferase, two compounds were found to inhibit the enzyme both in vitro and in vivo , using a choline auxotroph yeast strain complemented with the plasmodial enzyme [319].…”

Profiling the Essential Nature of Lipid Metabolism in Asexual Blood and Gametocyte Stages of Plasmodium falciparum

“…Fatty acids (FAs), the building blocks of lipids, are typically taken up from the human host by ABS parasites, in contrast to mosquito-resident stages that require de novo FA synthesis (van Schaijk et al, 2014). Potent antimalarial activity has been observed with compounds that target membrane or signaling lipids such as phosphatidylcholine (PC), phosphoethanolamine (PE) or phosphatidylinositol (PI) 4-phosphate (Bobenchik et al, 2013; Gonzalez-Bulnes et al, 2011; McNamara et al, 2013). …”