Antimalarial Drugs and Drug Targets Specific to Fatty Acid Metabolic Pathway of Plasmodium falciparum

Abstract

Plasmodium falciparum, a causitive agent of malaria, is the third most prevalent factor for mortility in the world. Falciparum malaria is an example of evolutionary and balancing selection. Because of mutation and natural selection, the parasite has developed resistance to most of the existing drugs. Under such circumstances, there is a growing need to develop new molecular targets in P. falciparum. A four membrane bound organelles called apicoplast, very much similar to that of chloroplast of plants, have been found in parasite. Therefore, the proteins involved in metabolic pathways of apicoplasts are important drug targets. Among the pathways in apicoplast, fatty acid biosynthetic pathway is the most important metabolic pathway in P. falciparum. Several studies have explored the role of different proteins involved in this pathway and antimalarial compounds against this target. In this review, we have studied the role of different proteins in fatty acid metabolism and designing, synthesis and evaluation of compounds against the targets identified in fatty acid metabolic pathway. Malaria is the global health problem and causes worldwide morbidity and mortality. Approximately, 300-500 million clinical cases and one million deaths caused per year worldwide due to malaria (1). Four Plasmodium species (P. vivax, P. ovale, P. malariae, and P. falciparum) are responsible for human malaria. Out of these, P. falciparum species causes most fatal form of malaria. This parasite has a plastid like organelle called as apicoplast. Resistance to known antimalarial and the lack of an effective vaccine have created an urgent need to discover new biologically active compounds. A four-membrane plastid organelle, the apicoplast is present in many apicomplexan parasites including P. falciparum, and apicoplast is believed to have arisen through endosymbiosis of an algal cell that had previously incorporated a cyanobacterium (2). The sequencing of the P. falciparum genome coupled with a detailed analysis of the proteins of known function, which were targeted to the apicoplast, allowed the construction of an apicoplast specific metabolic map (3). Several metabolic pathways exist in apicoplast, differing significantly from those found in the human host, based on its prokaryotic origin and has been considered as potential drug target for new therapeutics (4). Fatty acid biosynthetic pathway is the most important pathway in apicoplast. Most eukaryotes have type I fatty acid synthase (FAS) enzymes, which are large multifunctional enzymes composed of one or two polypeptides. Malaria parasites of the genus Plasmodium do not contain FAS and rely instead on a type II fatty acid synthase (FAS II) for the de novo production of fatty acids. Seven proteins found in the P. falciparum genome comprise a dissociated FAS II (5). The FAS II of P. falciparum is composed of six discrete enzymes, and the acyl carrier protein (ACP) serves to shuttle the nascent fatty acid among the enzymes of pathway. The apicoplast of parasite is the site for FAS II biosyn...

In silico screening for Plasmodium falciparum enoyl-ACP reductase inhibitors

“…Yu and co-workers demonstrated that knockouts of various FAS components in P. falciparum and rodent parasite Plasmodium berghei do not inhibit blood-stage growth (12). While exogenous FAs are sufficient for membrane biogenesis in the blood stage (13), recent studies revealed that de novo biosynthesis is exclusively required in the liver stage of the malarial life cycle (12, 14). Few antimalarial drugs, including atovaquone, primaquine, and anti-folates, are effective against both the blood- and liver-stage parasites.…”

Novel Type II Fatty Acid Biosynthesis (FAS II) Inhibitors as Multistage Antimalarial Agents

“…The lead compounds identified are structurally different from other inhibitors of FAS in malaria parasites (for a recent Review, see Ref. [28]). Compared with primaquine, the gold-standard, compounds 6g and 5j show at least a fivefold enhanced inhibitory effect on both the development of clinically silent liver-stage as well as disease-inducing erythrocytic blood-stage P. falciparum parasites.…”

Celastrol inhibits Plasmodium falciparum enoyl-acyl carrier protein reductase

“…11 In the blood stage, merozoites infect red-blood cells, initiating a replication process that requires exogenous (host-derived) FA to support membrane biogenesis. 12 It was previously thought that both the liver and blood stages of the malarial parasite relied on the uptake of FA from the host. 13,14 However, this paradigm was challenged when FA enzymes ( Fab H, Fab Z, Fab F) capable of de novo biosynthesis were found targeted to the apicoplast, a vestigial nonphotosynthetic plastid.…”

“…19,28–30 Though the efficacy of some FAS inhibitors against the blood stage is poorly understood, 19 inhibition of the late liver stage, which requires FAS, is thought to be promising for prophylactics. 8,11,12 …”