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Keywords:

  • antimalarials;
  • apicoplast;
  • DNA sequence variations;
  • fatty acid biosynthesis;
  • metabolic pathway

Abstract

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

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 biosynthesis, non-mevalonate pathway of isoprenoid biosynthesis, and synthesis of heme intermediates (2, 4, 6). DNA replication, transcription, and translation processes within the apicoplast are also validated drug targets (7). Among various pathways in apicoplast, fatty acid biosynthesis is the most studied metabolic pathway. All six enzymes and PfACP have been produced as pure recombinant proteins and characterized in a variety of assays (8–12). Lee et al. (13) reported the importance of fatty acids in P. falciparum.

The fatty acid chain extension step of FAS II is catalyzed by four key enzymes, Beta-ketoacyl ACP synthase I/II (FabB/F), β-ketoacyl-ACP reductase (FabG), enoyl-ACP reductase (Fab I), and β-hydroacyl-ACP dehydratase (FabZ) and the substrate/product of each reaction is covalently bound to the ACP cofactor Figure 1. The mammalian FAS pathway utilizes a single enzyme complex and is not present in Plasmodium. This is not common for all apicomplexan parasites, and the genome of Toxoplasma gondii encodes both FAS and FAS II enzymes. Cryptosporidium parvum has FAS enzyme, whereas Theileria annulata does not harbor either FAS or FAS II pathways (14). Mazumdar et al. (14) reported that apicoplast fatty acid synthesis is essential for organelle biogenesis and parasite survival by deletion of ACP from T. gondii. The P. falciparum enzymes have been expressed in vitro and used to reconstitute the elongation module of FAS II (15). Vial et al. (16) reported that erythrocytic stage of malarial parasites scavenges the majority of their fatty acids from the host. Probably, the FAS serves for the production of lipoate. Lipoic acid is a cofactor that is indispensable for the function of key enzyme complexes involved in oxidative metabolism such as pyruvate dehydrogenase (PDH). In P. falciparum, all four subunits of PDH have been exclusively localized to the apicoplast (17) and the E2 subunit has been shown to be covalently modified with lipoate (18). Although lipoate can be scavenged from the host, scavenged lipoate is not trafficked to the apicoplast and remain attached to PDH (18). Thus, apicoplast lipoate is derived from other sources. Although other pathways have been suggested for lipoate, all of them rely on fatty acids produced by FAS II. Some compounds have been screened as inhibitors against different P. falciparum enzyme and three of them are structurally characterized to aid in drug discovery efforts (19–21). In 2010, Ben Mamoun et al.(5) also reported the information of FAS II as an important drug target for the treatment of malaria.

image

Figure 1.  Diagramatic representation of fatty acid metabolism in Plasmodium falciparum. Fatty acid biosynthesis is divided in to two parts, fatty acid synthesis and fatty acid elongation cycle (A) Fatty acid biosynthesis (B) Elongation phase of Fatty acid synthesis along with inhibitors (45).

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In this review, we have summarized a recent advancement that cover the role of different proteins involved in P. falciparum fatty acid biosynthesis and designing, synthesis and evaluation of compounds that inhibit these target proteins.

Malaria Parasite Requires FAS II for Late Liver Stage Development

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

There are two distinct replicating life cycle forms of malarial parasite in human. After inoculation of sporozoite stages by the infected mosquito bite, a massive one-time replication occurs in the liver resulting in the production and release of 10 000 infectious exo-erythrocytic merozoites (22). These merozoites infect red blood cells and initiate the cyclic replication that occurs within the blood stream. This replication of parasite requires a plentiful lipid supply, specifically fatty acids for the membrane biogenesis. The parasites initially lack ability to synthesize their own fatty acids and thus take the lipids from their hosts. Surolia and Surolia (23) identified a Plasmodium FabI and showed that the FabI inhibitor triclosan kills blood stage parasites, and subsequently a significant effort has been undertaken to develop blood stage FAS II inhibitors to treat malaria (24,25). A liver stage transcriptome and proteome analysis in Plasmodium yoelii were carried out and findings were concluded that (i) the transcription of FAS II genes was increased in liver stages when compared with blood stages; (ii) FAS II enzymes were present in the liver stage proteome; and (iii) hexachlorophene (an inhibitor of FabG) was able to inhibit liver stage development in vitro (26). The results of the study suggested that FAS II might be important for parasite liver infection. Gene knockouts of FabB/F and FabZ demonstrated that FAS II is critical for normal liver stage development but not for blood stage or mosquito stage development. Gene knockout of FabI from P. falciparum, a further enzyme involved in FAS II, demonstrated that FAS II is not critical for P. falciparum blood stage replication.

It has been showed in a rodent malaria model that FAS II enzymes localize to the sporozoite and liver stage apicoplast (27). Targeted deletion of FabB/F did not affect parasite blood stage replication, mosquito stage development, and initial infection in the liver. This was confirmed by knockout of FabZ. Deletion of FabI in P. falciparum did not show a reduction in asexual blood stage replication in vitro. Therefore P. falciparum depends on the intrinsic FAS II pathway only at one specific life cycle transition point from liver to blood. The apicoplast-targeted FAS II is only necessary for Plasmodium late liver stage development. So in all other stages of life cycle, either the parasite synthesizes fatty acids by a yet unidentified de novo pathway or the parasite is able to scavenge all the fatty acids it requires from the host. Studies of the effect of triclosan on several microorganisms have concluded that the interaction of triclosan with the bacterial cell is complex and its lethality cannot be explained solely by the inhibition of metabolic pathways such as FAS II (28). Thus, triclosan could kill P. falciparum blood stages by inhibiting a vital process other than FAS II. It is possible that PDH is solely required by the apicoplast for the formation of acetyl CoA, which is subsequently utilized by FAS II. The results concerning liver stage development were generated with the rodent malaria parasite P. yoelii, but because of high conservation of FAS II among Plasmodium species suggests that FAS II is also essential for P. falciparum liver stage development (29). Therefore FAS II is considered as a promising antimalarial drug target.

Self-Acylation Properties of FAS II

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

Acyl carrier proteins are small acidic proteins having 80–100 amino acids and play a central role in metabolic processes involving acyl group transfer such as fatty acid biosynthesis, polyketide biosynthesis, and non-ribosomal peptide synthesis (30). Role played by ACP as a cofactor has been reported for the transfer of fatty acids to the lipid A portion of lipopolysaccharide of Gram-negative bacterial membranes (31), rhizobial capsular polysaccharide biosynthesis, and the production of Nod factors in rhizobia (32). Acyl carrier protein can exist as an integral component of a large FAS complex present in mammals, fungi, and certain mycobacteria, or an independent protein as in FAS II or dissociative-type fatty acid biosynthesis found in most bacteria, plants, and some apicomplexans (33). Acyl carrier protein is generally expressed in the apo form and undergoes post-translational modification to form active holo form by the addition of 4′-phosphopantetheine (4′-PP) moiety to an absolutely conserved serine residue, catalyzed by holo-ACP synthase (ACPS) or 4′-PP transferase (P-pant transferase) (34). The 3D structure of Escherichia coli ACP is a prototype of bacterial and plant ACP structures. FAS ACPs have an unusual dynamic equilibrium between two conformers (35), while only a single conformation is observed in the case of ACP of polyketide synthase (PKS). The absence of a discrete malonyl CoA: ACP transacylase (MCAT) in the polyketide II biosynthesis gene cluster led many groups to propose the involvement of FAS MCAT in polyketide biosynthesis. A variety of polyketide II synthesis ACPs were subject to non-MCAT-catalyzed acylation in the presence of malonyl-CoA (36). Moreover, self-acylation is not inherent to PKS II ACPs only, but is also shown by certain ACPs (P. falciparum ACP and Brassica napus chloroplast targeted ACP) involved in FAS II fatty acid biosynthesis (37). Unlike the PKS ACPs, only dicarboxylic acids, such as malonyl, succinyl, and glutaryl-CoAs, were used as substrates in FAS ACPs. Self-acylation properties in ACPs from P. falciparum and B. napus that are essential components of FAS II, disproving the existing phenomenon restricted only to ACPs involved in polyketide biosynthesis. It is also suggested that these FAS II ACPs exhibit a high degree of selectivity for self-acylation employing only dicarboxylic acids as substrates.

ACP is central to FAS II pathway and all ACPs contain a flexible phosphopantetheine prosthetic group derived from coenzyme A, and attached to a conserved serine residue. Holo-ACP synthase, an enzyme known to attach the phosphopantetheine group, post-translationally, converting apo-ACP into holo-ACP. PfACP has been localized exclusively to the apicoplast in P. falciparum. PfACP contains a phosphopantetheine prosthetic group (38) and played a role as a cofactor for fatty acid biosynthesis enzymes in reduced monomeric state. Inactivity of FAS during the blood stage indicates that acyl-PfACP is probably not synthesized (39). As glutathione biosynthesis occurs in the cytosol of P. falciparum, PfACP-glutathione mixed disulfides are probably not formed in the apicoplast of the parasite. The study by Gallagher and Prigge (40) also suggested that fatty acid biosynthesis occurs in the apicoplast organelle during the liver stage of the P. falciparum life cycle. Fatty acid biosynthesis is inactive and the redox state of the apicoplast has not been determined during the blood stage. The disulfide-linked form of PfACP even under conditions of oxidative stress has not been detected in parasite lysate, although a monomeric form of PfACP is present in parasite lysate. The apicoplast is a reducing compartment as suggested by models of P. falciparum metabolism and that PfACP is maintained in a reduced state during blood stage growth (40). Upadhyay et al. (41) carried out structural studies on the acyl-ACP intermediates of P. falciparum using NMR as a spectroscopic probe. The study provides insights into the molecular mechanism of ACP expansion, as revealed from a unique side chain-to-backbone hydrogen bond between two fairly conserved residues, Ile-55 HN and Glu-48 O. The studies also demonstrate the existence of malonyl transferase activity in ACPs involved in type II fatty acid biosynthesis from P. falciparum and E. coli. The catalytic malonyl transferase activity is intrinsic to an individual ACP. Mutational analysis implicates an arginine/lysine in loop II and an arginine/glutamine in helix III as the catalytic residues for transferase function.

Pyruvate Dehydrogenase

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

Pyruvate dehydrogenase activity is essential for progression of P. falciparum from liver to blood infection. Pyruvate dehydrogenase complex catalyzes the conversion of pyruvate to acetyl-CoA that acts as precursor for the tricarboxylic acid cycle and FAS II pathway. A single PDH enzyme complex, localized to apicoplast of P. falciparum and Plasmodium lacks a mitochondrial PDH. Pei et al. (42) reported that PDH E1 alpha and E3 subunits co-localize with the FAS II enzyme FabI in the apicoplast of liver stages but are not significantly expressed in blood stages in a rodent malaria model. Deletion of the E1 alpha or E3 subunit genes of P. yoelii PDH caused no defect in blood stage development, mosquito stage development or early liver stage development. This study strongly supports the hypothesis that the PDH serve to provide acetyl-CoA for FAS II (42).

Lactate Dehydrogenase Enzyme

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

The lactate dehydrogenase enzyme (LDH) of P. falciparum has been considered as a potential antimalarials target because of their role in glycolysis for energy production. The LDH enzymes found in P. vivax, P. malariae, and P. ovale (pLDH) all exhibit 90% identity to LDH. Penna-Coutinho et al. (43) performed docking studies to select potential inhibitors of pLDH, which were then tested for antimalarial activity against P. falciparum in vitro and P. berghei malaria in mice. Fifty compounds were selected based on their similarity to NADH. The compounds with the best binding energies (itraconazole, atorvastatin, and posaconazole) were tested against P. falciparum chloroquine-resistant blood parasites. All three compounds proved to be active in two immuno-enzymatic assays and IC50 values for each drug in both tests were similar but the lowest for posaconazole (Figure 2).

image

Figure 2.  Itraconazole conformation (shown as yellow) and NADH (shown as red) in the active site pocket of Plasmodium falciparum lactate dehydrogenase (PfLDH) enzyme (43).

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Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

Mitochondrion and the apicoplast both are considered as the most important organelles in P. falciparum and are integral to their metabolism (44). Both organelles contain an enzyme that requires lipoic acid as cofactor for their catalytic activity. These are the a-keto acid dehydrogenase complexes and the glycine cleavage system (GCS). The PDH is solely reported in the apicoplast whereas a-keto glutarate and branched chain a-keto acid dehydrogenase as well as the GCS are in mitochondria of the parasites. The study by Gunther et al. (44) revealed that the apicoplast located lipoic acid protein ligase, octanoyl-[acyl carrier protein] protein N-octanoyl transferase (LipB) is not essential for parasite survival by disrupting the LipB gene. Despite a drastic loss of total lipoic acid, the parasites progress through their intra erythrocytic development, although the apicoplast-located PDH shows a reduced level of lipoylation. Lipoic acid (LA) is an essential cofactor of a-keto acid dehydrogenase complexes (KADHs) and the glycine cleavage system. However, disruption of the LipB gene did not negatively affect parasite growth despite a drastic loss of LA (90%). Apicoplast-located PDH still showed lipoylation, suggesting that an alternative lipoylation pathway exists in this organelle. Dual targeted, functional lipoate protein ligase 2 (LplA2) plays a role in lipoylation and localization studies showed that LplA2 is present in both mitochondrion and apicoplast.

β-Ketoacyl-ACP Synthase I/II (PfFabB/F)

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

The fatty acid elongation is carried out by four enzymes among them β-ketoacyl-ACP synthase I/II (PfFabB/F) is one. E. coli has two isoforms for the elongation condensing enzymes (FabB and FabF) whereas Plasmodium has only one isoform. Sharma, et al. (45) reported that enzymes involved in condensing play an important role in fatty acid composition of organism. Morgan-Kiss, et al. (46) reported that the genome of Lactococcus lactis encodes a single long chain 3-ketoacyl-acyl carrier protein synthase. This is in contrast to its close relative, Enterococcus faecalis and to E. coli, both of which have two such enzymes. Expression of L. lactis FabF can functionally replace both FabB and FabF in E. coli, although it does not restore thermal regulation of phospholipid fatty acid composition to E.coli fabF mutant strains.

Conformational stability and thermodynamic characterization of homotetrameric P. falciparumβ-ketoacyl-ACP reductase (FabG) were shown by studies of Karmodiya et al. (47). The conformational stability of FabG was determined by guanidinium chloride-induced isothermal and thermal denaturation. The reversible unfolding transitions were monitored by intrinsic fluorescence, circular dichroism (CD) spectroscopy, and by measuring the enzyme activity of FabG. The denaturation profiles were analyzed to obtain the thermodynamic parameters associated with the unfolding of the protein. This study provides a prototype for determining conformational stability of other members of the short-chain alcohol dehydrogenase/reductase superfamily to which PfFabG also belongs.

Studies suggest that Triclosan is minimally effective in rodent malaria models (48). P. falciparum FAS II pathway is unique in terminating at C14 acyl chain and no other organism showed this property. Surolia et al. (48) found that triclosan inhibits FAS with a half-maximal inhibitory concentration of ∼800 nm, impeding blood-stage parasitic growth.

Similarly, the computational studies of P. falciparum metabolism were studied by Huthmacher et al. (49), which revealed a compartmentalized metabolic model and predicted life cycle stage specific metabolism with the help of a flux balance approach by integrating gene expression data. Predicted metabolite exchanges between parasite and host were found to be in good accordance with experimental findings when the parasite metabolic network was embedded into its host (erythrocyte).

β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

FAS II pathway in P. falciparum uses ACP and two enzymes. Acyl carrier protein transacylase (MCAT) catalyzes the formation of malonyl-ACP from malonyl-coenzyme A. PfKASIII catalyzes the condensation of malonyl-ACP and acetyl-CoA, forming a β-ketoacetyl–ACP product. The crystal structure of FabH has been determined and several FabH inhibitors, mostly based on the natural product Thiolactomycin, have been reported (50). FAS II systems of Mycobacterium tuberculosis, Staphylococcus aureus, and Pastuerella multocida were used as target for inhibition by Thiolactomycin and its analogs.

β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

The β-hydroxyacyl-acyl carrier protein dehydratase of P. falciparum (FabZ) catalyzes the third and important reaction of the fatty acid elongation cycle. The crystal structure of FabZ is available in hexameric (active) and dimeric (inactive) forms. Maity et al. (51) have designed a new condition to crystallize FabZ with its inhibitors bound in the active site and also determined the crystal structures of four of these complexes. In the crystal structures, residue Phe169 located in the middle of the tunnel was found to be in two different conformations, open and closed. Thus, Phe169, merely by changing its side chain conformation, appears to be controlling the length of the tunnel to make it suitable for accommodating longer substrates. This report on the crystal structures of the complexes of FabZ provides the structural basis of the inhibitory mechanism of enzyme. Tasdemira et al. (52) synthesized 2-hexadecynoic acids (HDAs) as antimalarial agents against the FabZ (Figure 3).

image

Figure 3.  The presentation of interaction of acetylenic ligands with PfFabZ and PfFabI predicted by docking (A) shows interaction of ligands within the binding site of PfFabZ (2-HAD represented as thick sticks inside the surface, green lines depict hydrogen bonds) (B) represents surface map of electrostatic potentials of the PfFabI with ligands bound to the multiple binding sites (2-HDA – green; 5-HDA – orange; 6-HDA – cyan) (52).

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Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

Approaches to antimalarial chemotherapy

Antimalarial drug design and discovery involve following approaches: (i) optimize therapy with existing agents such as amodiaquine, sulfadoxine, pyrimethamine, chloroquine, artemisinine, artemether, arteether, artesunate, mefloquine, lumefantrine, clindamycin, tetracyclines, quinolones, fosmidomycin, thiolactomycin, triclosan etc. and (ii) develop analogs of existing agents and natural products.

Optimization of therapy with existing agents

A first approach is to optimize therapy with existing agents. New dosing regimens or formulations may optimize antimalarial activity. Combination therapies, including newer agents (e.g. artemisinin derivatives, atovaquone) and new combinations of older agents (e.g. amodiaquine/sulfadoxine/pyrimethamine/chlorproguanil/dapsone/clindamycin/tetracyclines/quinolones/fosmidomycin/thiolactomycin/triclosan) are under study as first-line therapies for Africa and other areas with widespread antimalarial drug resistance.

Development of analogs of existing agents

Another approach to antimalarial chemotherapy is to improve upon existing antimalarials by chemical modifications of these compounds. This approach does not require knowledge of the mechanism of action or the biological target of the parent compound. Indeed, this approach was responsible for the development of many existing antimalarials. For example, chloroquine, primaquine, and mefloquine were discovered through chemical strategies to improve upon quinine.

Natural products

Plant-derived compounds offer a third approach to chemotherapy. Importantly, this approach can benefit from knowledge of medicinal plants among natives of malarious regions, where the appreciation of the use of plant products to treat febrile illnesses has grown over many generations. The first antimalarial drug was quinine, isolated from the bark of Cinchona species (Rubiaceae). In 1940, another antimalarial drug chloroquine was synthesized. Artemisinin a plant-based antimalarial drug was isolated from the Chinese plant Artemisia annua. It is a peroxide-bridged sesquiterpene lactone compound. Semi-synthetic derivatives of artemisinin, obtained by structural modifications of artemisinin are also available. These derivatives of artemisinin are more frequently used in malaria chemotherapy, because of their better pharmacokinetic properties and higher efficacies than the parent artemisinin compound. The most widely used artemisinin derivatives are artesunate, artemether, and dihydroartemisinin (artenimol, DHA). Others include arteether (artemotil) and artelinic acid. Although artemisinin derivatives are effective against the Plasmodium parasite (as monotherapies), combination therapies consisting of artemisinins and other standard antimalaria drugs have been demonstrated to have better parasite clearance and efficacies. These artemisinin-based combination therapies (ACTs) include: artesunate + amodiaquine, artemether + lumefantrine, artesunate + sulfadoxine + pyrimethamine, and artesunate + mefloquine. Previous reports have described artemisinin derivatives to be generally safe and well-tolerated. However, there are concerns about their potentials for neuro- and reproductive toxicities. In addition, previous toxicological studies on artemisinins evaluated their effects on specific systems, limiting such studies to make qualitative safety evaluations of these drugs. The two most widely used antimalarial drugs, chloroquine and sulfadoxine/pyrimethamine, are failing at an accelerating rate in most malaria-endemic regions owing to the development of resistance to these agents. Other antimalarial drugs such as mefloquine, halofantrine, atovaquone, proguanil, artemether, and lumefantrine retain efficacy but have limitations such as high cost. The drugs currently used for malaria come from three families: the quinolines (quinine, chloroquine, mefloquine, primaquine), the antifolates (sulfadoxine, pyrimethamine), and the artemisinin derivatives. Currently, there is a rapid spread of parasite drug resistance, mainly among the P. falciparum strains, resulting in an urgent need for new effective drugs with new mechanisms of action. This goal can be achieved in two ways either by focusing on validated targets in order to generate new drug candidates; or by identifying new potential targets for malaria chemotherapy. The advent of functional genomics and structure-based drug design should help in the search for new targets.

Beside Artemisinin, several other natural and synthetic compounds have been evaluated against the proteins of fatty acid pathway. Bhattarai et al. (53) reported that malaria prevalence has been reduced by insecticide treated bed nets and artemisinin-based combination drug therapy. Recently, Artemisinin drug resistance has already been detected and threatens to reverse reductions in malaria prevalence (54). The current chemotherapy against P. falciparum malaria uses one of the above approaches.

Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

Antimalarial analogs of triclosan inhibiting PfENR were developed. Triclosan substituted at 2′ position (The Cl at position 2′ in ring B of triclosan was chemically substituted with NH (2), NO (2) functional groups) was used to inhibit PfENR as studied by Kapoor et al. (55). A number of compounds are screened, synthesized, and evaluated for their potencies to inhibit (Table 1). Among them, two compounds, 2-(2′-Amino-4′-chloro-phenoxy)-5-chloro-phenol (compound 4) and 5-chloro-2-(4′-chloro-2′-nitro-phenoxy)-phenol) (compound 5) exhibited good potencies. Compound 4 followed uncompetitive inhibition kinetics with crotonoyl CoA and competitive with NADH. Compounds 4 and 5 showed significant inhibition of the parasite growth in P. falciparum culture. Studies by Frecer, et al. (56) showed that substituted analogs of triclosan (TCL) inhibit the purified PfENR enzyme with IC50 below 200 nm when the suboptimal 5-chloro group was replaced by larger hydrophobic moieties. TCL analogs substituted at positions 5, 4′, and 2′ were predicted to contain compounds with PfENR inhibition potencies in the low nanomolar range and with favorable ADME properties.

Table 1.   Enzymes of fatty acid biosynthetic pathway and their inhibitors. Thumbnail image of

3D-QSAR studies on triclosan derivatives as PfENR inhibitors were performed by Shah and Siddiqi (57). Authors carried out 3D-QSAR studies on a training set of 53 structurally highly diverse analogs of triclosan to investigate the correlation of the structural properties of triclosan derivatives with the inhibition of the activity of PfENR by employing Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). The crystal structure bound conformation of triclosan was used as a template for aligning molecules. The probable binding mode conformations of other inhibitors were explored according to molecular docking and molecular mechanics poisson-boltzmann surface area (MM/PBSA) solvation free energy estimation methods using grid based linear Poisson-Boltzmann calculations. The studies provide information about geometric and electrostatic complementarities between ligands and receptor and provide useful information about designing novel triclosan derivatives for PfENR inhibition. A structure-based approach has been used by Freundlich et al. (58) to develop 4′-substituted analogs of triclosan that target the PfENR. Many of these compounds exhibit nanomolar potency against purified PfENR enzyme and the modest (2–10 μm) potency against in vitro cultures of drug-resistant and drug-sensitive strains of the P. falciparum.

Affinity of PfENR Increases for Triclosan in the Presence of NAD+

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

Presence of some compounds altered the binding of triclosan to PfENR. The binding of the substrate analogue crotonoyl-CoA and coenzyme NADH to PfENR was studied by Kapoor et al. (59). A 300-fold increase in the binding constant in the presence of NAD+ has been reported. The dramatic enhancement in the binding affinity of both triclosan and NAD+ in the ternary complex can be explained by increased Van-der-Waals contacts in the ternary complex, facilitated by the movement of residues 318–324 of the substrate-binding loop and the nicotinamide ring of NAD+. The results provide a rationale for the increased affinity of NAD+ for the enzyme in the ternary complex.

Role of Green Tea Catechins in Triclosan Binding to PfENR

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

The mechanism involved in the inhibition of PfENR by triclosan in the presence of catechins and related plant polyphenols has been explained (60). The steady-state kinetics revealed time dependent inhibition of PfENR by triclosan, demonstrating that triclosan exhibited slow tight-binding kinetics with PfENR in the presence of these compounds. The high affinities of tea catechins and the potentiation of binding of triclosan in their presence are readily explained by molecular modeling studies. The triclosan potency enhancement induced by such compounds holds great promise for the development of effective antimalarial therapy.

Rhodanine inhibitors for PfENR were used by Kumar et al. (61). A number of new inhibitors belonging to rhodanine class have been identified and divided into two subclasses: rhodanine-furans and rhodanine-phenyls. The inhibitory activity of all compounds was determined against purified PfENR. Separate 3D pharmacophore models for this enzyme have been generated for both rhodanine furans and phenyls. The pharmacophore model for rhodanine furan has a Hydrogen bond donor, two Hydrogen bond acceptors, two metal ligators, three hydrophobic, and two aromatic ring features, whereas the pharmacophore model for the phenyl subclass has two hydrogen bond donors, two hydrogen bond acceptor, a metal ligator, two hydrophobic, and two aromatic ring features (61).

Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

It has been reported that Marine natural products from the Turkish sponge Agelas oroides inhibit PfENR (62). The authors have reported that CHCl3 and the aq MeOH extracts of the Turkish marine sponge A. oroides yielded six pure metabolites [24-ethyl-cholest-5alpha-7-en-3-beta-ol (i), 4,5-dibromopyrrole-2-carboxylic acid methyl ester (ii), 4,5-dibromopyrrole-2-carboxylic acid (iii), (E)-oroidin (iv), 3-amino-1-(2-aminoimidazoyl)-prop-1-ene (v), taurine (vi)] and some minor, complex fatty acid mixtures (FAMA-FAMG). FAMA, consisting of a 1:2 mixture of (5Z,9Z)-5,9-tricosadienoic (vii) and (5Z,9Z)-5,9-tetracosadienoic (viii) acids, and FAMB composed of 8, (5Z,9Z)-5,9-pentacosadienoic (ix) and (5Z,9Z)-5,9-hexacosadienoic (x) acids in approximately 3:3:2 ratio were the most active PfFabI.

Some Novel Inhibitors Based on Different Compounds

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

A series of analogs of 2-tosylnaphthalene-1, 4-diol have been reported by Alhamadsheh et al. (63). These were found potent against the E. coli FabH enzyme. The inhibitors were also effective but to a lesser degree against the M. tuberculosis and P. falciparum FabH enzymes. Previous studies demonstrated that the sulfonyl group and naphthalene-1,4 diol were required for activity against all enzymes but the toluene portion could be significantly altered and leads to either the modest increases or decreases in activity against the three enzymes. The in vitro activity of the analogs against E. coli FabH parallels the in vivo activity against E. coli Tol C strain and many of the compounds were also shown to have antimalarial activity against P. falciparum.

Similarly, Chhibber et al. (64) designed some novel diphenyl ethers and determined their binding energies for PfENR. The promising compounds were synthesized and tested for their inhibitory activity against ENRs of P. falciparum as well as E. coli. The study of structure-activity relationship of these compounds paves the way for further improvements in the design of novel diphenyl ethers with improved activity against purified enzyme and the pathogens. Likewise, a series of compounds were studied for enzymatic inhibition against PfENR and also for growth inhibition of P. falciparum cell culture within an order of magnitude of triclosan (Figure 4) (65).

image

Figure 4.  Diagramatic representation of docking of Triclosan at the active site of PfENR (65).

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Similarly, three linear sesquiterpene lactones were reported from Anthemis auriculata, namely anthecotulide, 4-hydroxyanthecotulide and 4-acetoxyanthecotulide for specific inhibitory effects on FabI (PfENR) enzyme from three pathogenic microorganisms, P. falciparum (PfFabI), M. tuberculosis (MtFabI), and E. coli (EcFabI) (66). The compounds were also tested against two elongation enzymes from the plasmodial FAS II system, beta-ketoacyl-ACP reductase (PfFabG), and beta-hydroxyacyl-ACP deydratase (PfFabZ). The compounds showed clear differentiation in inhibition of FabI enzymes from different microorganisms. The study suggested that Anthecotulide was most active against MtFabI, whereas the oxygenated derivatives specifically inhibited plasmodial FAS II enzymes, PfFabI and PfFabG. All compounds were inactive towards EcFabI. In whole cell assays, all three compounds exhibited antimalarial and antibacterial activities.

Molecular modeling studies, synthesis, and biological evaluation of PfENR inhibitors were studies by Morde et al. (67). PfENR (FabI) is one of the important enzymes in fatty acid biosynthetic pathway that has a determinant role in completing chain elongation. The ligand was selected and modified to optimize its binding with PfENR. The analogs of N-benzylidene-4-phenyl-1, 3-thiazol-2-amine were developed for inhibition of PfENR. The activity of these analogs was predicted from CoMFA and CoMSIA models constructed from a dataset of 43 known inhibitors of PfENR. The most promising molecules were synthesized and their structures characterized by spectroscopic techniques. The molecules were screened for in vitro antimalarial activity and molecules namely, VRC-007 and VRC-009 were reported to be active.

Antiadhesion therapies for saving lives and studies to clarify the adhesion phenotypes causing severe malaria were studied by Simmons (68). Molecular mechanisms and therapeutic implications of adhesion of P. falciparum-infected erythrocytes to human cells were explored (69). Recently, a phenotypic forward chemical genetic approach to assay 309 474 chemicals was used by Guiguemde et al. (70). Several of these chemicals showed potent in vitro activity against drug-resistant P. falciparum strains. A reverse chemical genetic study identified 19 new inhibitors of four validated drug targets and 15 novel binders among 61 malarial proteins.

Benzothiophene Derivatives as Inhibitors of PfENR

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

Studies showed that Benzothiophene derivatives (benzothiophene sulphonamides, biphenyls, or carboxyls) were synthesized as antimalarials (71). Studies suggest that Bromo-benzothiophene carboxamide derivatives as potent inhibitors of PfENR. 3-Bromo-N-(4-fluorobenzyl)-benzo[b]thiophene-2-carboxamide considered as most potent inhibitor with an IC50 of 115 nm for purified PfENR.

Novel Inhibitors of Toxoplasma gondii Enoyl Reductase

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

Significant morbidity and mortality are caused by Toxoplasmosis, and under such circumstances improved drugs are needed urgently. In this direction, rational approaches were used to identify novel lead compounds effective against Toxoplasma gondii enoyl reductase (TgENR), a FASII fatty acid synthase enzyme essential in parasites but not present in animals. The 53 compounds, including three classes that inhibit ENRs, were tested (72). Six compounds have antiparasite MIC90s ≤6 μm without toxicity to host cells, three compounds have IC90s <45 nm against recombinant TgENR, and two protect mice.

Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

The PfKASIII inhibitors fall into three new chemotypes (sulfides, sulfonamides, and sulfonyls). The bacterial FabH as an antibacterial drug target resulted in the identification of several new classes of inhibitors against P. falciparum malaria (63). These inhibitors showed different sensitivity between bacterial FabH and PfKASIII (50). Studies have demonstrated that PfKASI/II is more sensitive to thiolactomycin than PfKASIII (10). The compounds isolated from natural products have potent inhibition effect on both FabH and FabF. Current antimalarial therapies employ the strategy of combining two or more inhibitors to slow the development of malaria drug resistance. A compound that inhibits both malaria KAS enzymes could work on the same pattern.

Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

The inhibitors based on Thiolactomycin against the fatty acid elongation enzymes, β-ketoacyl-ACP synthases I, II, and III (FabB, FabF and FabH, respectively) were reported by Waller et al. (73). The natural product thiolactomycin inhibits bacterial β-ketoacyl-ACP synthase enzymes (FabH, FabB, and FabF) and inhibited the growth of P. falciparum with an IC50 value of 50 μm.

In recent studies, CoMFA, CoMSIA, and docking studies were performed on Thiolactone-class of antimalarials against Fab enzyme (74). Pharmacophore with two hydrogen-bond acceptor and one aromatic hydrophobic feature has been generated using seven active flavonoids by Gupta et al. (75). Docking studies of these compounds well corroborate with the pharmacophore model. This model could be useful for identification of potential novel FAS II inhibitors.

In another studies, synthesis of 2-, 5-, 6-, and 9-HDAs and its in vitro evaluation against erythrocytic (blood) stages of P. falciparum and liver stages of P. yoelii infections were performed (52). The inhibitory potential of the HDAs against multiple P. falciparum FAS II elongation enzymes was evaluated. The highest antiplasmodial activity against blood stages of P. falciparum was displayed by 5-HDA (IC50 = 6.6 μg/mL). 2-HDA showed the best inhibitory activity against the PfFASII enzymes PfFabI and PfFabZ with IC50 0.38 and 0.58 μg/ml respectively. Lack of cytotoxicity, lipophilic nature, and calculated pharmacokinetic properties suggest that 2-HDA could be a useful compound to study the interaction of fatty acids with P. falciparum FASII enzymes.

Contribution of Host Genetic Factor in Falciparum Malaria

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

Infectious disease and evolution

Falciparum malaria belongs to evolutionary selection and example of balanced polymorphisms. Small changes in the genome may be selected so as to combat pathogen attack. There are many examples in evolutionary history where naturally occurring genetic defense mechanisms have evolved for resisting infectious diseases. A number of red cell defects like Sickle cell trait, thalassemia, Duffy antigen variation, and G6PD deficiency, which also confer resistance to the malaria parasite, are classical examples of genetic footprints selected by the disease pressure of malaria, one of the strongest known forces of evolutionary selection on human genome. Another finding is the introduction of a 32-base deletion in the CCR-5 gene (gene for a chemokine receptor), which protects the individual from HIV disease progression. While studying the co-evolution of species, it is important not only to consider the genetic makeup of the host but also that of the pathogen. When any infectious agent attacks the human host, it immediately encounters its defense machinery and microenvironments. In a scenario where infectious agents have many evolutionary advantages due to their short generation time, high fecundity, and mutation rates, the host immune mechanism needs to employ effective strategies to fight the invading pathogen. The pathogen is under strong selection to constantly devise new strategies for gaining access to the host while evading its defense system which is often modulated and modified by the administration of antibiotics. Plasmodium falciparum malaria is an example of evolutionary selection. Both host and parasite show the phenomenon of natural selection.

Glucose 6 phosphate dehydrogenase

Glucose 6 phosphates dehydrogenase is an enzyme that converts glucose 6 phosphate into 6 phospho glucono gamma lactone in the oxidative branch of pentose phosphate pathway and generates NADPH. This NADPH prevents the oxidative stress in the erythrocytes. Mutation in the gene that encodes the glucose 6 phosphate Dehydrogenase results in reduced enzyme activity and has been implicated in malarial resistance. It is the best example of balancing selection in the human genome. G6PD is an important housekeeping enzyme and plays a critical role in maintaining the balance of reduced nicotinamide adenine dinucleotide phosphate NADPH, necessary cofactor for cell detoxification. Erythrocytes deficient of G6PD cannot produce NADPH and reduced glutathione thus impairing the cell’s ability to combat oxidative damage caused by free radicals ultimately resulting in hemolysis. The P. falciparum parasite, during its erythrocytic cycle, produces free radicals as a result of metabolism which may cause hemolysis in the absence of G6PD and hence the death of parasite. Because of such reason, the G6PD deficiency is maintained as a balanced polymorphism in malaria hyper-endemic regions worldwide.

Pyruvate kinase deficiency

In humans, pyruvate kinase deficiency is the second most common erythrocyte enzyme disorder. Report showed that pyruvate kinase deficiency provides protection against infection and replication of P. falciparum in human erythrocytes, raising the possibility that mutant pyruvate kinase alleles may confer a protective advantage against malaria in human populations in areas where the disease is endemic.

Duffy blood antigen

FY gene that encodes a protein called Duffy antigen, which serve as chemokine receptor, and is expressed in various cell types. This Duffy antigen is expressed in erythrocytes of most populations but not sub Saharan Africa. Duffy antigen might act as a receptor of the P. vivax parasite. A single base pair mutation at −46 positions in the FYB gene, which impairs its promoter activity in RBCs by disrupting the GATA1 biding site results in the FyB phenotype. The FyB phenotype or the FYO allele is incapable of binding the P. vivax parasite.

Hemoglobin variants

Malaria is a type of evolutionary selection. In response to disease pressure, human genome selects variations in the genes related to RBC structure and function so as to confer resistance to malaria. Alpha globin is encoded by identical HBA1 and HBA2, and beta globin is encoded by HBB. HBB has three different coding SNPs each confer resistance against malaria in sub-Saharan Africa as well as Middle East and central India, and the populations have single base substitution at codon 6 resulting in the substitution of glutamic acid to valine in beta globin chain, which give rise to sickled cell hemoglobin. The carriers of HbS trait, the heterozygotes, are apparently healthy and are protected against malaria and thus this hemoglobin defect is maintained in high frequency in the form of balanced polymorphism in many malaria-endemic populations. Various clinical studies and epidemiological data have shown that heterozygotes for HbS are about 90% protected against severe form of malaria including cerebral malaria (76) with 60% protection against mortality observed in infants (77). Several studies suggest that HbAS and HbAC (Heterozygous states of hemoglobin A and HbS (HbAS, sickle-cell trait) or HbC (HbAC) accelerate the acquisition of immunity to malaria, possibly by enhancing P. falciparum-specific antibody responses. HbAS and HbAC protect against malaria by enhancing antibody responses to antigens through other immune mechanisms and not by enhancing P. falciparum-specific antibody responses (78). In India, the HbS is mostly concentrated in Central India, in the states of Maharashtra, Andhra Pradesh, Orissa, and parts of Gujarat and Rajasthan. Orissa being hyperendemic for malaria, alone shows ∼30% of HbS carrier frequency distribution between tribal and various caste groups (79). Another structural variant of hemoglobin is HBC, which is found in several parts of West Africa but it is less common than HBS. It confers resistance against malaria in both homozygotes as well as hetrozygotes state but a greater protective effect has been reported in homozygotes. This is based on the observation of reduced parasite cytoadharance, abnormal PfEMP1 expression, clustering of erythrocyte band 3 protien, and altered erythrocyte membrane in the presence of hemoglobin C. Hemoglobin E is common in South East Asia. Homozygotes generally have symptom less anemia. It has been observed that erythrocytes from HbE-hetrozygous individuals are relatively resistance to invasion by P. falciparum.

Thalassemias

The Thalassemia resulted due to defective production of alpha or beta globin chains. This condition may rises due to deletions or other disruption of globin gene clusters on chromosome 11 and 16. The α- and β-thalassemias are consequence of deletions or point mutations in the non-coding portion of the globin genes and cause inadequate synthesis of the α- and β-globin chains. The patients suffering from thalassemia have resistant against malaria.

Genetically based alterations conferring protection against malaria have led to co-adaptation of various human populations with widespread malaria parasites. This co-adaptative process has resulted in benefits for host (protection) and parasite (reduced virulence/chronicity) (80).

DNA sequence variation and drug response

The genetic polymorphism in P. falciparum at 10 loci is considered as potential targets for specific antimalarial vaccines (81). The polymorphism is unevenly distributed among the loci; loci encoding proteins expressed on the surface of the sporozoite or the merozoite (AMA-1, CSP, LSA-1, MSP-1, MSP-2, and MSP-3) are more polymorphic than those expressed during the sexual stages or inside the parasite (EBA-175, Pfs25, PF48/45, and RAP-1). Comparison of synonymous and non-synonymous substitutions indicates that natural selection may account for the polymorphism observed at seven of the 10 loci studied. This inference depends on the assumption that synonymous substitutions are neutral. There are evidences for an overall trend towards increasing A+T richness, but no evidence found for mutation biasness. Although the neutrality of synonymous substitutions is not definitely established, this trend towards an A+T rich genome cannot explain the accumulation of substitutions at least in the case of four genes (AMA-1, CSP, LSA-1, and PF48/45) because the G[RIGHTWARDS ARROW]C transversions are more frequent than expected. There is definite evidence for positive natural selection in the genes encoding AMA-1, CSP, LSA-1, MSP-1, and Pfs48/45. For four other loci, EBA-175, MSP-2, MSP-3, and RAP-1, the evidence is limited. No evidence for natural selection has been found for Pfs25 (81). The study of DNA sequence variation in both host and parasite plays an important role in drug response. Genetic variation associated with increased susceptibility to complex diseases can elucidate genes and underlying biochemical mechanisms linked to disease onset and progression. In cases where gene is associated with disease, the most common condition is that genetic variation or causal mutations alter an encoded protein sequence. But a significant number of undiscovered causal mutations may alter the regulation of gene transcription. However, it remains a challenge to separate causal genetic variations from linked neutral variations. One of the most important applications of genetic polymorphisms is the drug response. Presence of Polymorphisms (DNA sequence variations) may affect the severity of disease and alters the response to a particular drug (Figure 5). My study (82–85) clearly indicates that how host polymorphisms play a role in P. falciparum malaria. So study of polymorphisms is very important for detection of drug response (Figure 6).

image

Figure 5.  Diagramatic representation of role of polymorphisms in drug response.

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image

Figure 6.  Flow chart representing theme of review.

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Discussion

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

The immense success of drug discovery efforts prompted the view that many infectious diseases would now be effectively controlled and even eradicated. Drug resistance arises through the unrelenting pressure of natural selection, and this requires a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms. The pressing need for novel adjunctive therapies to lower the mortality rate from severe malaria argues strongly for further research in this area. Development of new drugs is one of the strategies for malaria control. The pathway for the synthesis of fatty acids in Plasmodium is an excellent target for the design of novel antimalarial agents. PfENR is one of the important enzymes in this pathway, and several studies have focused work on the design of some novel molecules that would serve as inhibitors of PfENR. The design of new molecules was initiated with in silico methods of docking, virtual screening of databases, and 3D-QSAR based prediction of molecules activity by using CoMFA and CoMSIA models. β-Ketoacyl-ACP synthases I and II (KASI/FabB) is another important enzyme of this pathway. Current vaccines are based on a handful of proteins, and several of which were first described several decades ago and before analysis of P. falciparum genome indicated that there are about 5400 protein-coding genes, some of which are expressed in an exquisitely stage-specific manner and others that are not. Recent comparative genomic studies in CSIR-Central Institute of Medicinal & Aromatic Plants, Lucknow, India (CIMAP Annual Report 2009–2010; http://www.cimap.res.in) revealed prediction of 751 unique or essential genes/proteins as potential antimalarial drug targets specific to P. falciparum 3D7. A proteome set of total of 5269 proteins of P. falciparum was compared against human genome/proteome, out of which 4518 protein sequences showed similarity with human proteome and rest 751 proteins showed no match. These unmatched 751 genes/proteins considered very specific to malarial parasite and required for survival of parasite, therefore, could be the future drug targets against malarial parasite. Out of these 751 unique protein sequences, after functional annotation 141 proteins were predicted functionally known, 241 proteins with unknown function (i.e., <30% sequence similarity while studying through BLASTp at NCBI server, USA; http://www.ncbi.nlm.nih.gov/), and 368 hypothetical proteins/genes (i.e., 30–40% protein sequence similarity with GenBank (NCBI) database sequences through BLASTp) were reported by Feroz Khan (CSR-CIMAP Annual Report, 2009–2010). Out of known unique proteins 7.5% belongs to transcription factor category, 15.11% belongs to Plasmodium exported proteins, 21.15% to membrane proteins, 7.5% belongs to merozoite proteins, 29.2% belongs to erythrocyte membrane proteins, 8.6% belongs to antigenic proteins, 3.2% belongs to transporter class, 16.11% belongs to enzymes category, and 36.25% belongs to other important proteins. Details of Plasmodium genome resource data are available at PlasmoDB database (http://plasmodb.org/plasmo/).

Antimalarial drug therapy focuses on three families of compounds: the quinolines (chloroquine, quinine, amodiaquine, mefloquine, halofantrine), the antifolates (sulfadoxine-pyrimethamine), and the Sesquiterpene lactones e.g., artemisinin derivatives (Dihydroartemisinin, artemether, arteether/artemotil, and artesunate), all of which have great clinical significance but possess liabilities related to resistance, compliance, safety, cost, and/or ineffectiveness. To avoid an ever-increasing toll of malaria in India and other tropical countries, it is imperative to rapidly put into action a strategic plan for the discovery and development of novel antimalarial compounds that are not encumbered by existing mechanisms of drug resistance and related problems. More recently, an improved understanding of the biochemistry of malarial parasites has identified many potential targets for new drugs. Based on the analysis of these report, we have suggested that enzymes and proteins of fatty acid biosynthesis pathway are the promising drug targets in P. falciparum. Because of increase in the incidence of malaria, there is growing need for the identification and characterization of novel drug target in fatty acid biosynthetic pathway and designing of novel molecules based on existing inhibitors as well as some natural compounds having inhibition properties. The proteins of metabolic pathways in apicoplast are the most important antimalarial drug targets at present. Among these, fatty acid biosynthesis pathway remains one of the most important targets for developing novel drugs. It is clear by several reports that functional fatty acid synthesis pathways are absolutely required for parasite viability. The novel inhibitors of fatty acid synthesis enzymes from bacteria, plants, and humans will continue to provide a wealth of lead compounds for use in the development of apicomplexan specific drugs.

Future Perspective

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

Comparative genomics approach has given a large number of antimalarial drug targets and parasite has the ability to develop resistance to most of the existing drug targets frequently. It is well known that malaria shows balancing selection and several host genetic polymorphisms have been known to play significant role in falciparum malaria. Prediction of DNA sequence variations (polymorphisms) in genes involved in fatty acid metabolic pathway of P. falciparum and modeling of novel pharmacophore would be helpful in drug discovery process against Plasmodium parasite. There is close interaction between gene-gene and gene-environment. Most of the people are working with single nucleotide polymorphisms (SNP) and copy number variations and their role in disease (case control study). The consideration of role of polymorphisms (DNA sequence variation) in drug response would be more helpful in drug designing. There should be more focus on copy number variation, microsatellite repeat, and single nucleotide polymorphisms and their effect on novel antimalarial compounds. The study of interactions among the polymorphisms and their role in drug response would be more effective. The study of such aspect would open the new avenues in field of drug designing.

References

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information
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Author Information

  1. Top of page
  2. Abstract
  3. Malaria Parasite Requires FAS II for Late Liver Stage Development
  4. Self-Acylation Properties of FAS II
  5. Pyruvate Dehydrogenase
  6. Lactate Dehydrogenase Enzyme
  7. Apicoplast Lipoic Acid Protein Ligase B Is Not Essential for Plasmodium falciparum
  8. β-Ketoacyl-ACP Synthase I/II (PfFabB/F)
  9. β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  10. β-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ)
  11. Chemotherapy: Compounds against Plasmodium falciparum proteins of Fatty Acid Metabolic Pathway
  12. Compounds against Enoyl-ACP Reductase of Plasmodium falciparum (PfENR)
  13. Affinity of PfENR Increases for Triclosan in the Presence of NAD+
  14. Role of Green Tea Catechins in Triclosan Binding to PfENR
  15. Marine Natural Products from the Turkish Sponge Agelas oroides as Inhibitor of PfENR
  16. Some Novel Inhibitors Based on Different Compounds
  17. Benzothiophene Derivatives as Inhibitors of PfENR
  18. Novel Inhibitors of Toxoplasma gondii Enoyl Reductase
  19. Compounds against β-Ketoacyl–Acyl Carrier Protein Synthase III (PfKASIII)
  20. Compounds against β-ketoacyl-ACP Synthase I/II (PfFabB/F)
  21. Contribution of Host Genetic Factor in Falciparum Malaria
  22. Discussion
  23. Future Perspective
  24. Acknowledgments
  25. Conflict of interest
  26. References
  27. Author Information

Mohammad Tabish Qidwai did his MTech degree in Biotechnology from Gautam Buddh Technical University (formerly, U.P. Tech. Univ.), Lucknow (India) in 2007 and MSc Biochemistry (Gold Medalist) from Dr. R. M. L. Avadh University, Faizabad in 2003. He is presently doing PhD work in Biotechnology from G.B. Tech. Univ., Lucknow. He has qualified UGC-CSIR NET examination. He has also qualified GATE examination and received its fellowship from AICTE, New Delhi during MTech degree. He has done research work on ‘Study of host polymorphisms in genes related to Plasmodium falciparum infection in an endemic region of India’ under the supervision of Dr. Saman Habib Scientist E-II, Division of Molecular & Structural Biology, CSIR-Central Drug Research Institute, Lucknow (India). He has published few research papers in reputed journals. He has delivered few invited lectures in Biotechnology area in different research institutes/universities of India.

Dr. Feroz Khan, did MTech (Biotechnology) and PhD in Bioinformatics from Institute of Engg. & Tech., Uttar Pradesh Tech. University (now G.B. Tech. Univ.), Lucknow, India. He has been awarded with prestigious Council of Scientific & Industrial Research (CSIR) – Senior Research Fellowship (SRF) 2004. He is presently working as Scientist, CSIR-Central Institute of Medicinal & Aromatic Plants, (CSIR, Department of Scientific & Industrial Research, Ministry of Science & Technology, Government of India, New Delhi), Lucknow, India since 2007. He has published more than 20 research papers in reputed journals. He has delivered more than 20 invited lectures in both Biotechnology and Bioinformatics area in different research institutes/universities of India. His area of interest is molecular binding affinity studies through sequence and structure based modeling using statistical and machine learning (ANN and SVM) approaches. He has developed different sequence based model for the identification of transcription factors binding sites in genes upstream DNA sequences e.g., nod-box, PhoB-box, SOS-box, PurR-box, Dre-box, Abre-box etc. He has also developed few activity prediction models for plant derived natural compounds/derivatives using drug likeness filter, bioavailability filter, toxicity filter and QSAR/QSPR/QSTR approaches. Also predict the binding affinity of compounds through molecular docking as proven by his publications. Presently he is working in lead optimization and drug targets identification related to anti-inflammatory, immuno-modulatory, anti-cancer, anti-malaria, anti-fungal and anti-bacterial.