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Chamboko, Chiratidzo R., Wayde Veldman, Rolland Bantar Tata, Birgit Schoeberl, and Özlem Tastan Bishop. "Human Cytochrome P450 1, 2, 3 Families as Pharmacogenes with Emphases on Their Antimalarial and Antituberculosis Drugs and Prevalent African Alleles." International Journal of Molecular Sciences 24, no. 4 (February 8, 2023): 3383. http://dx.doi.org/10.3390/ijms24043383.
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Precision medicine gives individuals tailored medical treatment, with the genotype determining the therapeutic strategy, the appropriate dosage, and the likelihood of benefit or toxicity. Cytochrome P450 (CYP) enzyme families 1, 2, and 3 play a pivotal role in eliminating most drugs. Factors that affect CYP function and expression have a major impact on treatment outcomes. Therefore, polymorphisms of these enzymes result in alleles with diverse enzymatic activity and drug metabolism phenotypes. Africa has the highest CYP genetic diversity and also the highest burden of malaria and tuberculosis, and this review presents current general information on CYP enzymes together with variation data concerning antimalarial and antituberculosis drugs, while focusing on the first three CYP families. Afrocentric alleles such as CYP2A6*17, CYP2A6*23, CYP2A6*25, CYP2A6*28, CYP2B6*6, CYP2B6*18, CYP2C8*2, CYP2C9*5, CYP2C9*8, CYP2C9*9, CYP2C19*9, CYP2C19*13, CYP2C19*15, CYP2D6*2, CYP2D6*17, CYP2D6*29, and CYP3A4*15 are implicated in diverse metabolic phenotypes of different antimalarials such as artesunate, mefloquine, quinine, primaquine, and chloroquine. Moreover, CYP3A4, CYP1A1, CYP2C8, CYP2C18, CYP2C19, CYP2J2, and CYP1B1 are implicated in the metabolism of some second-line antituberculosis drugs such as bedaquiline and linezolid. Drug–drug interactions, induction/inhibition, and enzyme polymorphisms that influence the metabolism of antituberculosis, antimalarial, and other drugs, are explored. Moreover, a mapping of Afrocentric missense mutations to CYP structures and a documentation of their known effects provided structural insights, as understanding the mechanism of action of these enzymes and how the different alleles influence enzyme function is invaluable to the advancement of precision medicine.
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Sharma, Shilpi, Shailendra Kumar Sharma, Rahul Modak, Krishanpal Karmodiya, Namita Surolia, and Avadhesha Surolia. "Mass Spectrometry-Based Systems Approach for Identification of Inhibitors of Plasmodium falciparum Fatty Acid Synthase." Antimicrobial Agents and Chemotherapy 51, no. 7 (May 7, 2007): 2552–58. http://dx.doi.org/10.1128/aac.00124-07.
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ABSTRACT The emergence of strains of Plasmodium falciparum resistant to the commonly used antimalarials warrants the development of new antimalarial agents. The discovery of type II fatty acid synthase (FAS) in Plasmodium distinct from the FAS in its human host (type I FAS) opened up new avenues for the development of novel antimalarials. The process of fatty acid synthesis takes place by iterative elongation of butyryl-acyl carrier protein (butyryl-ACP) by two carbon units, with the successive action of four enzymes constituting the elongation module of FAS until the desired acyl length is obtained. The study of the fatty acid synthesis machinery of the parasite inside the red blood cell culture has always been a challenging task. Here, we report the in vitro reconstitution of the elongation module of the FAS of malaria parasite involving all four enzymes, FabB/F (β-ketoacyl-ACP synthase), FabG (β-ketoacyl-ACP reductase), FabZ (β-ketoacyl-ACP dehydratase), and FabI (enoyl-ACP reductase), and its analysis by matrix-assisted laser desorption-time of flight mass spectrometry (MALDI-TOF MS). That this in vitro systems approach completely mimics the in vivo machinery is confirmed by the distribution of acyl products. Using known inhibitors of the enzymes of the elongation module, cerulenin, triclosan, NAS-21/91, and (−)-catechin gallate, we demonstrate that accumulation of intermediates resulting from the inhibition of any of the enzymes can be unambiguously followed by MALDI-TOF MS. Thus, this work not only offers a powerful tool for easier and faster throughput screening of inhibitors but also allows for the study of the biochemical properties of the FAS pathway of the malaria parasite.
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Hariharan, Jayashree, Rajendra Rane, Kasirajan Ayyanathan, Philomena, Vidya Prasanna Kumar, Dwarkanath Prahlad, and Santanu Datta. "Mechanism-Based Inhibitors: Development of a High Throughput Coupled Enzyme Assay to Screen for Novel Antimalarials." Journal of Biomolecular Screening 4, no. 4 (August 1999): 187–92. http://dx.doi.org/10.1177/108705719900400406.
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Identifying potent enzyme inhibitors through a robust HTS assay is currently thought to be the most efficient way of searching for lead molecules. We have developed a HTS assay that mimics a crucial step in an essential metabolic pathway, the purine salvage pathway of the malarial parasite Plasmodium falciparum. In this assay we have used purified recombinant enzymes: hypoxanthine guanine phosphoribosyl transferase (HGPRT) and inosine monophosphate dehydrogenase (IMPDH) from the malarial parasite and the human host, respectively. These two enzymes, which work in tandem, are used to set up a coupled assay that is robust enough to meet the stringent criteria of an HTS assay. In the first phase of our screen we seem to have identified novel inhibitors that kill the parasite by inhibiting the salvage pathway of the parasite.
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Drinkwater, Nyssa, Komagal Kannan Sivaraman, Rebecca S. Bamert, Wioletta Rut, Khadija Mohamed, Natalie B. Vinh, Peter J. Scammells, Marcin Drag, and Sheena McGowan. "Structure and substrate fingerprint of aminopeptidase P from Plasmodium falciparum." Biochemical Journal 473, no. 19 (September 27, 2016): 3189–204. http://dx.doi.org/10.1042/bcj20160550.
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Malaria is one of the world's most prevalent parasitic diseases, with over 200 million cases annually. Alarmingly, the spread of drug-resistant parasites threatens the effectiveness of current antimalarials and has made the development of novel therapeutic strategies a global health priority. Malaria parasites have a complicated lifecycle, involving an asymptomatic ‘liver stage’ and a symptomatic ‘blood stage’. During the blood stage, the parasites utilise a proteolytic cascade to digest host hemoglobin, which produces free amino acids absolutely necessary for parasite growth and reproduction. The enzymes required for hemoglobin digestion are therefore attractive therapeutic targets. The final step of the cascade is catalyzed by several metalloaminopeptidases, including aminopeptidase P (APP). We developed a novel platform to examine the substrate fingerprint of APP from Plasmodium falciparum (PfAPP) and to show that it can catalyze the removal of any residue immediately prior to a proline. Further, we have determined the crystal structure of PfAPP and present the first examination of the 3D structure of this essential malarial enzyme. Together, these analyses provide insights into potential mechanisms of inhibition that could be used to develop novel antimalarial therapeutics.
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Piedade, Rita, Stefanie Traub, Andreas Bitter, Andreas K. Nüssler, José P. Gil, Matthias Schwab, and Oliver Burk. "Carboxymefloquine, the Major Metabolite of the Antimalarial Drug Mefloquine, Induces Drug-Metabolizing Enzyme and Transporter Expression by Activation of Pregnane X Receptor." Antimicrobial Agents and Chemotherapy 59, no. 1 (October 13, 2014): 96–104. http://dx.doi.org/10.1128/aac.04140-14.
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ABSTRACTMalaria patients are frequently coinfected with HIV and mycobacteria causing tuberculosis, which increases the use of coadministered drugs and thereby enhances the risk of pharmacokinetic drug-drug interactions. Activation of the pregnane X receptor (PXR) by xenobiotics, which include many drugs, induces drug metabolism and transport, thereby resulting in possible attenuation or loss of the therapeutic responses to the drugs being coadministered. While several artemisinin-type antimalarial drugs have been shown to activate PXR, data on nonartemisinin-type antimalarials are still missing. Therefore, this study aimed to elucidate the potential of nonartemisinin antimalarial drugs and drug metabolites to activate PXR. We screened 16 clinically used antimalarial drugs and six major drug metabolites for binding to PXR using the two-hybrid PXR ligand binding domain assembly assay; this identified carboxymefloquine, the major and pharmacologically inactive metabolite of the antimalarial drug mefloquine, as a potential PXR ligand. Two-hybrid PXR-coactivator and -corepressor interaction assays and PXR-dependent promoter reporter gene assays confirmed carboxymefloquine to be a novel PXR agonist which specifically activated the human receptor. In the PXR-expressing intestinal LS174T cells and in primary human hepatocytes, carboxymefloquine induced the expression of drug-metabolizing enzymes and transporters on the mRNA and protein levels. The crucial role of PXR for the carboxymefloquine-dependent induction of gene expression was confirmed by small interfering RNA (siRNA)-mediated knockdown of the receptor. Thus, the clinical use of mefloquine may result in pharmacokinetic drug-drug interactions by means of its metabolite carboxymefloquine. Whether thesein vitrofindings are ofin vivorelevance has to be addressed in future clinical drug-drug interaction studies.
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Tselios, K., D. D. Gladman, Jiandong Su, and M. B. Urowitz. "Antimalarials as a risk factor for elevated muscle enzymes in systemic lupus erythematosus." Lupus 25, no. 5 (November 18, 2015): 532–35. http://dx.doi.org/10.1177/0961203315617845.
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KAPOOR, Mili, C. Chandramouli REDDY, M. V. KRISHNASASTRY, Namita SUROLIA, and Avadhesha SUROLIA. "Slow-tight-binding inhibition of enoyl-acyl carrier protein reductase from Plasmodium falciparum by triclosan." Biochemical Journal 381, no. 3 (July 27, 2004): 719–24. http://dx.doi.org/10.1042/bj20031821.
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Triclosan is a potent inhibitor of FabI (enoyl-ACP reductase, where ACP stands for acyl carrier protein), which catalyses the last step in a sequence of four reactions that is repeated many times with each elongation step in the type II fatty acid biosynthesis pathway. The malarial parasite Plasmodium falciparum also harbours the genes and is capable of synthesizing fatty acids by utilizing the enzymes of type II FAS (fatty acid synthase). The basic differences in the enzymes of type I FAS, present in humans, and type II FAS, present in Plasmodium, make the enzymes of this pathway a good target for antimalarials. The steady-state kinetics revealed time-dependent inhibition of FabI by triclosan, demonstrating that triclosan is a slow-tight-binding inhibitor of FabI. The inhibition followed a rapid equilibrium step to form a reversible enzyme–inhibitor complex (EI) that isomerizes to a second enzyme–inhibitor complex (EI*), which dissociates at a very slow rate. The rate constants for the isomerization of EI to EI* and the dissociation of EI* were 5.49×10−2 and 1×10−4 s−1 respectively. The Ki value for the formation of the EI complex was 53 nM and the overall inhibition constant Ki* was 96 pM. The results match well with the rate constants derived independently from fluorescence analysis of the interaction of FabI and triclosan, as well as those obtained by surface plasmon resonance studies [Kapoor, Mukhi, N. Surolia, Sugunda and A. Surolia (2004) Biochem. J. 381, 725–733].
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Ericsson, Therese, Collen Masimirembwa, Angela Abelo, and Michael Ashton. "The Evaluation of CYP2B6 Inhibition by Artemisinin Antimalarials in Recombinant Enzymes and Human Liver Microsomes." Drug Metabolism Letters 6, no. 4 (July 1, 2013): 247–57. http://dx.doi.org/10.2174/1872312811206040004.
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Opoku, Francis, Penny P. Govender, Ofentse J. Pooe, and Mthokozisi B. C. Simelane. "Evaluating Iso-Mukaadial Acetate and Ursolic Acid Acetate as Plasmodium falciparum Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase Inhibitors." Biomolecules 9, no. 12 (December 11, 2019): 861. http://dx.doi.org/10.3390/biom9120861.
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To date, Plasmodium falciparum is one of the most lethal strains of the malaria parasite. P. falciparum lacks the required enzymes to create its own purines via the de novo pathway, thereby making Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPT) a crucial enzyme in the malaria life cycle. Recently, studies have described iso-mukaadial acetate and ursolic acid acetate as promising antimalarials. However, the mode of action is still unknown, thus, the current study sought to investigate the selective inhibitory and binding actions of iso-mukaadial acetate and ursolic acid acetate against recombinant PfHGXPT using in-silico and experimental approaches. Recombinant PfHGXPT protein was expressed using E. coli BL21 cells and homogeneously purified by affinity chromatography. Experimentally, iso-mukaadial acetate and ursolic acid acetate, respectively, demonstrated direct inhibitory activity towards PfHGXPT in a dose-dependent manner. The binding affinity of iso-mukaadial acetate and ursolic acid acetate on the PfHGXPT dissociation constant (KD), where it was found that 0.0833 µM and 2.8396 µM, respectively, are indicative of strong binding. The mode of action for the observed antimalarial activity was further established by a molecular docking study. The molecular docking and dynamics simulations show specific interactions and high affinity within the binding pocket of Plasmodium falciparum and human hypoxanthine-guanine phosphoribosyl transferases. The predicted in silico absorption, distribution, metabolism and excretion/toxicity (ADME/T) properties predicted that the iso-mukaadial acetate ligand may follow the criteria for orally active drugs. The theoretical calculation derived from ADME, molecular docking and dynamics provide in-depth information into the structural basis, specific bonding and non-bonding interactions governing the inhibition of malarial. Taken together, these findings provide a basis for the recommendation of iso-mukaadial acetate and ursolic acid acetate as high-affinity ligands and drug candidates against PfHGXPT.
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SUROLIA, Avadhesha, T. N. C. RAMYA, V. RAMYA, and Namita SUROLIA. "‘FAS’t inhibition of malaria." Biochemical Journal 383, no. 3 (October 26, 2004): 401–12. http://dx.doi.org/10.1042/bj20041051.
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Malaria, a tropical disease caused by Plasmodium sp., has been haunting mankind for ages. Unsuccessful attempts to develop a vaccine, the emergence of resistance against the existing drugs and the increasing mortality rate all call for immediate strategies to treat it. Intense attempts are underway to develop potent analogues of the current antimalarials, as well as a search for novel drug targets in the parasite. The indispensability of apicoplast (plastid) to the survival of the parasite has attracted a lot of attention in the recent past. The present review describes the origin and the essentiality of this relict organelle to the parasite. We also show that among the apicoplast specific pathways, the fatty acid biosynthesis system is an attractive target, because its inhibition decimates the parasite swiftly unlike the ‘delayed death’ phenotype exhibited by the inhibition of the other apicoplast processes. As the enzymes of the fatty acid biosynthesis system are present as discrete entities, unlike those of the host, they are amenable to inhibition without impairing the operation of the host-specific pathway. The present review describes the role of these enzymes, the status of their molecular characterization and the current advancements in the area of developing inhibitors against each of the enzymes of the pathway.
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Ong, Wei-Yi, Mei-Lin Go, De-Yun Wang, Irwin Kee-Mun Cheah, and Barry Halliwell. "Effects of Antimalarial Drugs on Neuroinflammation-Potential Use for Treatment of COVID-19-Related Neurologic Complications." Molecular Neurobiology 58, no. 1 (September 8, 2020): 106–17. http://dx.doi.org/10.1007/s12035-020-02093-z.
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AbstractThe SARS-CoV-2 virus that is the cause of coronavirus disease 2019 (COVID-19) affects not only peripheral organs such as the lungs and blood vessels, but also the central nervous system (CNS)—as seen by effects on smell, taste, seizures, stroke, neuropathological findings and possibly, loss of control of respiration resulting in silent hypoxemia. COVID-19 induces an inflammatory response and, in severe cases, a cytokine storm that can damage the CNS. Antimalarials have unique properties that distinguish them from other anti-inflammatory drugs. (A) They are very lipophilic, which enhances their ability to cross the blood-brain barrier (BBB). Hence, they have the potential to act not only in the periphery but also in the CNS, and could be a useful addition to our limited armamentarium against the SARS-CoV-2 virus. (B) They are non-selective inhibitors of phospholipase A2 isoforms, including cytosolic phospholipase A2 (cPLA2). The latter is not only activated by cytokines but itself generates arachidonic acid, which is metabolized by cyclooxygenase (COX) to pro-inflammatory eicosanoids. Free radicals are produced in this process, which can lead to oxidative damage to the CNS. There are at least 4 ways that antimalarials could be useful in combating COVID-19. (1) They inhibit PLA2. (2) They are basic molecules capable of affecting the pH of lysosomes and inhibiting the activity of lysosomal enzymes. (3) They may affect the expression and Fe2+/H+ symporter activity of iron transporters such as divalent metal transporter 1 (DMT1), hence reducing iron accumulation in tissues and iron-catalysed free radical formation. (4) They could affect viral replication. The latter may be related to their effect on inhibition of PLA2 isoforms. Inhibition of cPLA2 impairs an early step of coronavirus replication in cell culture. In addition, a secretory PLA2 (sPLA2) isoform, PLA2G2D, has been shown to be essential for the lethality of SARS-CoV in mice. It is important to take note of what ongoing clinical trials on chloroquine and hydroxychloroquine can eventually tell us about the use of antimalarials and other anti-inflammatory agents, not only for the treatment of COVID-19, but also for neurovascular disorders such as stroke and vascular dementia.
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Fox, Robert I., and Ho-Il Kang. "Mechanism of Action of Antimalarial Drugs: Inhibition of Antigen Processing and Presentation." Lupus 2, no. 1_suppl (February 1993): 9–12. http://dx.doi.org/10.1177/0961203393002001031.
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Recent studies have elucidated the steps involved in the association of antigenic peptides with major histocompatibility complex (MHC) encoded proteins and have suggested how antimalarial compounds might influence this important site of immune activation. These steps of antigen presentation in the macrophage (or other antigen-presenting cells) include: (a) the partial proteolytic degradation of endogenous and exogenous proteins into peptides within the lysosome; (b) the synthesis of MHC class II (i.e. HLA-D associated) α, β, and invariant (Ii) chains in the endoplasmic reticulum; (c) the initial association of α-Ii and β-li chains in the endoplasmic reticulum and the transport of these complexes to the primary endosome; (d) the fusion of lysosomal vacuoles and endosomal vacuoles, allowing the mixtures of lysosomal enzymes, peptides, α–Ii and β–Ii; (e) the displacement of Ii chains by peptides to form α–β–peptide complexes in the endosome; and (f) the migration of α–β–peptide complexes to the macrophage cell surface where they can stimulate CD4 T cells, resulting in release of cytokines. A low pH is required for digestion of the protein by acidic hydrolases in the lysosome, for assembly of the α–β–peptide complex and for its transport to the cell surface. Chloroquine and hydroxychloroquine are weak diprotic bases that can diffuse across the cell membrane and raise the pH within cell vesicles. This background provides the underlying basis for the theory that antimalarials may act to prevent autoimmunity by the following putative mechanism. Antimalarial compounds may: (a) stabilize the α-Ii and β-Ii interactions and prevent low-affinity peptides from forming α–β–peptide complexes; and (b) interfere with the efficient movement of α-Ii, β-Ii and α–β–peptide complexes to the correct locations within the cell cytoplasm or to the cell surfaces. Decreased presentation of autoantigenic peptides by macrophages might then lead to downregulation of autoimmune CD4+ T cells and diminish release of cytokines associated with clinical and laboratory signs of autoimmune disease.
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Ericsson, Therese, Jesper Sundell, Angelica Torkelsson, Kurt-Jürgen Hoffmann, and Michael Ashton. "Effects of artemisinin antimalarials on Cytochrome P450 enzymesin vitrousing recombinant enzymes and human liver microsomes: potential implications for combination therapies." Xenobiotica 44, no. 7 (January 8, 2014): 615–26. http://dx.doi.org/10.3109/00498254.2013.878815.
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Lytton, SD, B. Mester, J. Libman, A. Shanzer, and ZI Cabantchik. "Mode of action of iron (III) chelators as antimalarials: II. Evidence for differential effects on parasite iron-dependent nucleic acid synthesis." Blood 84, no. 3 (August 1, 1994): 910–15. http://dx.doi.org/10.1182/blood.v84.3.910.910.
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Abstract Iron chelation treatment of red blood cells infected with Plasmodium falciparum selectively intervenes with iron-dependent metabolism of malaria parasites and inhibits their development. Highly permeant hydroxamate iron chelator RSFileum2 affects all parasite stages when cultures are continuously exposed to drug, but affects primarily ring stages when assessed for irreversible effects, ie, sustained inhibition remaining after drug removal. On the other hand, the hydrophilic and poorly permeant desferrioxamine (DFO) affects primarily trophozoite/schizont stages when tested either in the continuous mode or irreversible mode. Unlike parasites, mammalian cells subjected to similar drug treatment show complete growth recovery once drugs are removed. Our studies indicate that parasites display a limited capacity to recover from intracellular iron depletion evoked by iron chelators. Based on these findings we provide a working model in which the irreversible effects of RSFs on rings are explained by the absence of pathways for iron acquisition/utilization by early forms of parasites. Trophozoite/schizonts can partially recover from RSFileum2 treatments, but show no DNA synthesis following DFO treatment even after drug removal and iron replenishment by permeant iron carriers. At trophozoite stage, the parasite uses a limited pathway for refurnishing its iron-containing enzymes, thus overcoming iron deprivation caused by permeant RSFileum2, but not by DFO because this latter drug is not easily removable from parasites. Their DNA synthesis is blocked by the hydroxamate iron chelators probably by affecting synthesis of ribonucleotide reductase (RNRase). Presumably in parasites, prolonged repression of the enzyme leads also to irreversible loss of activity. The action profiles of RSFileum2 and DFO presented in this study have implications for improved chemotherapeutic performance by combined drug treatment and future drug design based on specific intervention at parasite DNA synthesis.
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Lytton, SD, B. Mester, J. Libman, A. Shanzer, and ZI Cabantchik. "Mode of action of iron (III) chelators as antimalarials: II. Evidence for differential effects on parasite iron-dependent nucleic acid synthesis." Blood 84, no. 3 (August 1, 1994): 910–15. http://dx.doi.org/10.1182/blood.v84.3.910.bloodjournal843910.
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Iron chelation treatment of red blood cells infected with Plasmodium falciparum selectively intervenes with iron-dependent metabolism of malaria parasites and inhibits their development. Highly permeant hydroxamate iron chelator RSFileum2 affects all parasite stages when cultures are continuously exposed to drug, but affects primarily ring stages when assessed for irreversible effects, ie, sustained inhibition remaining after drug removal. On the other hand, the hydrophilic and poorly permeant desferrioxamine (DFO) affects primarily trophozoite/schizont stages when tested either in the continuous mode or irreversible mode. Unlike parasites, mammalian cells subjected to similar drug treatment show complete growth recovery once drugs are removed. Our studies indicate that parasites display a limited capacity to recover from intracellular iron depletion evoked by iron chelators. Based on these findings we provide a working model in which the irreversible effects of RSFs on rings are explained by the absence of pathways for iron acquisition/utilization by early forms of parasites. Trophozoite/schizonts can partially recover from RSFileum2 treatments, but show no DNA synthesis following DFO treatment even after drug removal and iron replenishment by permeant iron carriers. At trophozoite stage, the parasite uses a limited pathway for refurnishing its iron-containing enzymes, thus overcoming iron deprivation caused by permeant RSFileum2, but not by DFO because this latter drug is not easily removable from parasites. Their DNA synthesis is blocked by the hydroxamate iron chelators probably by affecting synthesis of ribonucleotide reductase (RNRase). Presumably in parasites, prolonged repression of the enzyme leads also to irreversible loss of activity. The action profiles of RSFileum2 and DFO presented in this study have implications for improved chemotherapeutic performance by combined drug treatment and future drug design based on specific intervention at parasite DNA synthesis.
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Morales-Jadán, Diana, José Blanco-Salas, Trinidad Ruiz-Téllez, and Francisco Centeno. "Three Alkaloids from an Apocynaceae Species, Aspidosperma spruceanum as Antileishmaniasis Agents by In Silico Demo-case Studies." Plants 9, no. 8 (August 3, 2020): 983. http://dx.doi.org/10.3390/plants9080983.
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This paper is focused on demonstrating with a real case that Ethnobotany added to Bioinformatics is a promising tool for new drugs search. It encourages the in silico investigation of “challua kaspi”, a medicinal kichwa Amazonian plant (Aspidosperma spruceanum) against a Neglected Tropical Disease, leishmaniasis. The illness affects over 150 million people especially in subtropical regions, there is no vaccination and conventional treatments are unsatisfactory. In attempts to find potent and safe inhibitors of its etiological agent, Leishmania, we recovered the published traditional knowledge on kichwa antimalarials and selected three A. spruceanum alkaloids, (aspidoalbine, aspidocarpine and tubotaiwine), to evaluate by molecular docking their activity upon five Leishmania targets: DHFR-TS, PTR1, PK, HGPRT and SQS enzymes. Our simulation results suggest that aspidoalbine interacts competitively with the five targets, with a greater affinity for the active site of PTR1 than some physiological ligands. Our virtual data also point to the demonstration of few side effects. The predicted binding free energy has a greater affinity to Leishmania proteins than to their homologous in humans (TS, DHR, PKLR, HGPRT and SQS), and there is no match with binding pockets of physiological importance. Keys for the in silico protocols applied are included in order to offer a standardized method replicable in other cases. Apocynaceae having ethnobotanical use can be virtually tested as molecular antileishmaniasis new drugs.
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Kadian, Kavita, Yash Gupta, Harsh Vardhan Singh, Prakasha Kempaiah, and Manmeet Rawat. "Apicoplast Metabolism: Parasite’s Achilles’ Heel." Current Topics in Medicinal Chemistry 18, no. 22 (January 10, 2019): 1987–97. http://dx.doi.org/10.2174/1568026619666181130134742.
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Malaria continues to impinge heavily on mankind, with five continents still under its clasp. Widespread and rapid emergence of drug resistance in the Plasmodium parasite to current therapies accentuate the quest for novel drug targets and antimalarial compounds. Plasmodium parasites, maintain a non-photosynthetic relict organelle known as Apicoplast. Among the four major pathways of Apicoplast, biosynthesis of isoprenoids via Methylerythritol phosphate (MEP) pathway is the only indispensable function of Apicoplast that occurs during different stages of the malaria parasite. Moreover, the human host lacks MEP pathway. MEP pathway is a validated repertoire of novel antimalarial and antibacterial drug targets. Fosmidomycin, an efficacious antimalarial compound against IspC enzyme of MEP pathway is already in clinical trials as a combination drugs. Exploitation of other enzymes of MEP pathway would provide a much-needed impetus to the antimalarial drug discovery programs for the elimination of malaria. We outline the cardinal features of the MEP pathway enzymes and progress made towards the characterization of new inhibitors.
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Stirling, C. J. M. "Gordon Lowe. 31 May 1933 – 6 August 2003." Biographical Memoirs of Fellows of the Royal Society 51 (January 2005): 237–52. http://dx.doi.org/10.1098/rsbm.2005.0015.
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Gordon Lowe made major contributions to the understanding of the mechanisms of enzyme action, pioneering the use in particular of novel isotopically chiral phosphate and sulphate esters. In the latter part of his scientific work he discovered new peptide nucleic acids, probed the interaction of platinum complexes with enzymes, leading to potential new antimalarial drugs, and discovered, by combinatorial methods, effective active–site enzyme inhibitors.
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Potter, Brittney M. J., Lisa H. Xie, Chau Vuong, Jing Zhang, Ping Zhang, Dehui Duan, Thu-Lan T. Luong, et al. "Differential CYP 2D6 Metabolism Alters Primaquine Pharmacokinetics." Antimicrobial Agents and Chemotherapy 59, no. 4 (February 2, 2015): 2380–87. http://dx.doi.org/10.1128/aac.00015-15.
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ABSTRACTPrimaquine (PQ) metabolism by the cytochrome P450 (CYP) 2D family of enzymes is required for antimalarial activity in both humans (2D6) and mice (2D). Human CYP 2D6 is highly polymorphic, and decreased CYP 2D6 enzyme activity has been linked to decreased PQ antimalarial activity. Despite the importance of CYP 2D metabolism in PQ efficacy, the exact role that these enzymes play in PQ metabolism and pharmacokinetics has not been extensively studiedin vivo. In this study, a series of PQ pharmacokinetic experiments were conducted in mice with differential CYP 2D metabolism characteristics, including wild-type (WT), CYP 2D knockout (KO), and humanized CYP 2D6 (KO/knock-in [KO/KI]) mice. Plasma and liver pharmacokinetic profiles from a single PQ dose (20 mg/kg of body weight) differed significantly among the strains for PQ and carboxy-PQ. Additionally, due to the suspected role of phenolic metabolites in PQ efficacy, these were probed using reference standards. Levels of phenolic metabolites were highest in mice capable of metabolizing CYP 2D6 substrates (WT and KO/KI 2D6 mice). PQ phenolic metabolites were present in different quantities in the two strains, illustrating species-specific differences in PQ metabolism between the human and mouse enzymes. Taking the data together, this report furthers understanding of PQ pharmacokinetics in the context of differential CYP 2D metabolism and has important implications for PQ administration in humans with different levels of CYP 2D6 enzyme activity.
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Andrews, Katherine T., David P. Fairlie, Praveen K. Madala, John Ray, David M. Wyatt, Petrina M. Hilton, Lewis A. Melville, et al. "Potencies of Human Immunodeficiency Virus Protease Inhibitors In Vitro against Plasmodium falciparum and In Vivo against Murine Malaria." Antimicrobial Agents and Chemotherapy 50, no. 2 (February 2006): 639–48. http://dx.doi.org/10.1128/aac.50.2.639-648.2006.
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ABSTRACT Parasite resistance to antimalarial drugs is a serious threat to human health, and novel agents that act on enzymes essential for parasite metabolism, such as proteases, are attractive targets for drug development. Recent studies have shown that clinically utilized human immunodeficiency virus (HIV) protease inhibitors can inhibit the in vitro growth of Plasmodium falciparum at or below concentrations found in human plasma after oral drug administration. The most potent in vitro antimalarial effects have been obtained for parasites treated with saquinavir, ritonavir, or lopinavir, findings confirmed in this study for a genetically distinct P. falciparum line (3D7). To investigate the potential in vivo activity of antiretroviral protease inhibitors (ARPIs) against malaria, we examined the effect of ARPI combinations in a murine model of malaria. In mice infected with Plasmodium chabaudi AS and treated orally with ritonavir-saquinavir or ritonavir-lopinavir, a delay in patency and a significant attenuation of parasitemia were observed. Using modeling and ligand docking studies we examined putative ligand binding sites of ARPIs in aspartyl proteases of P. falciparum (plasmepsins II and IV) and P. chabaudi (plasmepsin) and found that these in silico analyses support the antimalarial activity hypothesized to be mediated through inhibition of these enzymes. In addition, in vitro enzyme assays demonstrated that P. falciparum plasmepsins II and IV are both inhibited by the ARPIs saquinavir, ritonavir, and lopinavir. The combined results suggest that ARPIs have useful antimalarial activity that may be especially relevant in geographical regions where HIV and P. falciparum infections are both endemic.
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Aroonsri, Aiyada, Navaporn Posayapisit, Jindaporn Kongsee, Onsiri Siripan, Danoo Vitsupakorn, Sugunya Utaida, Chairat Uthaipibull, Sumalee Kamchonwongpaisan, and Philip J. Shaw. "Validation of Plasmodium falciparum deoxyhypusine synthase as an antimalarial target." PeerJ 7 (April 17, 2019): e6713. http://dx.doi.org/10.7717/peerj.6713.
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Background Hypusination is an essential post-translational modification in eukaryotes. The two enzymes required for this modification, namely deoxyhypusine synthase (DHS) and deoxyhypusine hydrolase are also conserved. Plasmodium falciparum human malaria parasites possess genes for both hypusination enzymes, which are hypothesized to be targets of antimalarial drugs. Methods Transgenic P. falciparum parasites with modification of the PF3D7_1412600 gene encoding PfDHS enzyme were created by insertion of the glmS riboswitch or the M9 inactive variant. The PfDHS protein was studied in transgenic parasites by confocal microscopy and Western immunoblotting. The biochemical function of PfDHS enzyme in parasites was assessed by hypusination and nascent protein synthesis assays. Gene essentiality was assessed by competitive growth assays and chemogenomic profiling. Results Clonal transgenic parasites with integration of glmS riboswitch downstream of the PfDHS gene were established. PfDHS protein was present in the cytoplasm of transgenic parasites in asexual stages. The PfDHS protein could be attenuated fivefold in transgenic parasites with an active riboswitch, whereas PfDHS protein expression was unaffected in control transgenic parasites with insertion of the riboswitch-inactive sequence. Attenuation of PfDHS expression for 72 h led to a significant reduction of hypusinated protein; however, global protein synthesis was unaffected. Parasites with attenuated PfDHS expression showed a significant growth defect, although their decline was not as rapid as parasites with attenuated dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) expression. PfDHS-attenuated parasites showed increased sensitivity to N1-guanyl-1,7-diaminoheptane, a structural analog of spermidine, and a known inhibitor of DHS enzymes. Discussion Loss of PfDHS function leads to reduced hypusination, which may be important for synthesis of some essential proteins. The growth defect in parasites with attenuated Pf DHS expression suggests that this gene is essential. However, the slower decline of PfDHS mutants compared with PfDHFR-TS mutants in competitive growth assays suggests that PfDHS is less vulnerable as an antimalarial target. Nevertheless, the data validate PfDHS as an antimalarial target which can be inhibited by spermidine-like compounds.
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Breijyeh, Zeinab, and Rafik Karaman. "Enzyme Models—From Catalysis to Prodrugs." Molecules 26, no. 11 (May 28, 2021): 3248. http://dx.doi.org/10.3390/molecules26113248.
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Enzymes are highly specific biological catalysts that accelerate the rate of chemical reactions within the cell. Our knowledge of how enzymes work remains incomplete. Computational methodologies such as molecular mechanics (MM) and quantum mechanical (QM) methods play an important role in elucidating the detailed mechanisms of enzymatic reactions where experimental research measurements are not possible. Theories invoked by a variety of scientists indicate that enzymes work as structural scaffolds that serve to bring together and orient the reactants so that the reaction can proceed with minimum energy. Enzyme models can be utilized for mimicking enzyme catalysis and the development of novel prodrugs. Prodrugs are used to enhance the pharmacokinetics of drugs; classical prodrug approaches focus on alternating the physicochemical properties, while chemical modern approaches are based on the knowledge gained from the chemistry of enzyme models and correlations between experimental and calculated rate values of intramolecular processes (enzyme models). A large number of prodrugs have been designed and developed to improve the effectiveness and pharmacokinetics of commonly used drugs, such as anti-Parkinson (dopamine), antiviral (acyclovir), antimalarial (atovaquone), anticancer (azanucleosides), antifibrinolytic (tranexamic acid), antihyperlipidemia (statins), vasoconstrictors (phenylephrine), antihypertension (atenolol), antibacterial agents (amoxicillin, cephalexin, and cefuroxime axetil), paracetamol, and guaifenesin. This article describes the works done on enzyme models and the computational methods used to understand enzyme catalysis and to help in the development of efficient prodrugs.
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Cunningham, Eithne, Marcin Drag, Pawel Kafarski, and Angus Bell. "Chemical Target Validation Studies of Aminopeptidase in Malaria Parasites Using α-Aminoalkylphosphonate and Phosphonopeptide Inhibitors." Antimicrobial Agents and Chemotherapy 52, no. 9 (May 5, 2008): 3221–28. http://dx.doi.org/10.1128/aac.01327-07.
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ABSTRACT During its intraerythrocytic phase, the most lethal human malarial parasite, Plasmodium falciparum, digests host cell hemoglobin as a source of some of the amino acids required for its own protein synthesis. A number of parasite endopeptidases (including plasmepsins and falcipains) process the globin into small peptides. These peptides appear to be further digested to free amino acids by aminopeptidases, enzymes that catalyze the sequential cleavage of N-terminal amino acids from peptides. Aminopeptidases are classified into different evolutionary families according to their sequence motifs and preferred substrates. The aminopeptidase inhibitor bestatin can disrupt parasite development, suggesting that this group of enzymes might be a chemotherapeutic target. Two bestatin-susceptible aminopeptidase activities, associated with gene products belonging to the M1 and M17 families, have been described in blood-stage P. falciparum parasites, but it is not known whether one or both are required for parasite development. To establish whether inhibition of the M17 aminopeptidase is sufficient to confer antimalarial activity, we evaluated 35 aminoalkylphosphonate and phosphonopeptide compounds designed to be specific inhibitors of M17 aminopeptidases. The compounds had a range of activities against cultured P. falciparum parasites with 50% inhibitory concentrations down to 14 μM. Some of the compounds were also potent inhibitors of parasite aminopeptidase activity, though it appeared that many were capable of inhibiting the M1 as well as the M17 enzyme. There was a strong correlation between the potencies of the compounds against whole parasites and against the enzyme, suggesting that M17 and/or M1 aminopeptidases may be valid antimalarial drug targets.
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Pyatakova, N. V., and I. S. Severina. "Soluble guanylate cyclase in the molecular mechanism underlying the therapeutic action of drugs." Biomeditsinskaya Khimiya 58, no. 1 (January 2012): 32–42. http://dx.doi.org/10.18097/pbmc20125801032.
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The influence of ambroxol - a mucolytic drug - on the activity of human platelet soluble guanylate cyclase and rat lung soluble guanylate cyclase and activation of both enzymes by NO-donors (sodium nitroprusside and Sin-1) were investigated. Ambroxol in the concentration range from 0.1 to 10 μM had no effect on the basal activity of both enzymes. Ambroxol inhibited in a concentration-dependent manner the sodium nitroprusside-induced human platelet soluble guanylate cyclase and rat lung soluble guanylate cyclase with the IC50 values 3.9 and 2.1 μM, respectively. Ambroxol did not influence the stimulation of both enzymes by protoporphyrin IX.The influence of artemisinin - an antimalarial drug - on human platelet soluble guanylate cyclase activity and the enzyme activation by NO-donors were investigated. Artemisinin (0.1-100 μM) had no effect on the basal activity of the enzyme. Artemisinin inhibited in a concentration-dependent manner the sodium nitroprusside-induced activation of human platelet guanylate cyclase with an IC50 value 5.6 μM. Artemisinin (10 μM) also inhibited (by 71±4.0%) the activation of the enzyme by thiol-dependent NO-donor the derivative of furoxan, 3,4-dicyano-1,2,5-oxadiazolo-2-oxide (10 μM), but did not influence the stimulation of soluble guanylate cyclase by protoporphyrin IX. It was concluded that the sygnalling system NO-soluble guanylate cyclase-cGMP is involved in the molecular mechanism of the therapeutic action of ambroxol and artemisinin.
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Saliba, Kevin J., and Christina Spry. "Exploiting the coenzyme A biosynthesis pathway for the identification of new antimalarial agents: the case for pantothenamides." Biochemical Society Transactions 42, no. 4 (August 1, 2014): 1087–93. http://dx.doi.org/10.1042/bst20140158.
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Malaria kills more than half a million people each year. There is no vaccine, and recent reports suggest that resistance is developing to the antimalarial regimes currently recommended by the World Health Organization. New drugs are therefore needed to ensure malaria treatment options continue to be available. The intra-erythrocytic stage of the malaria parasite's life cycle is dependent on an extracellular supply of pantothenate (vitamin B5), the precursor of CoA (coenzyme A). It has been known for many years that proliferation of the parasite during this stage of its life cycle can be inhibited with pantothenate analogues. We have shown recently that pantothenamides, a class of pantothenate analogues with antibacterial activity, inhibit parasite proliferation at submicromolar concentrations and do so competitively with pantothenate. These compounds, however, are degraded, and therefore rendered inactive, by the enzyme pantetheinase (vanin), which is present in serum. In the present mini-review, we discuss the two strategies that have been put forward to overcome pantetheinase-mediated degradation of pantothenamides. The strategies effectively provide an opportunity for pantothenamides to be tested in vivo. We also put forward our ‘blueprint’ for the further development of pantothenamides (and other pantothenate analogues) as potential antimalarials.
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Teoh, Keat H., Devin R. Polichuk, Darwin W. Reed, and Patrick S. Covello. "Molecular cloning of an aldehyde dehydrogenase implicated in artemisinin biosynthesis in Artemisia annuaThis paper is one of a selection of papers published in a Special Issue from the National Research Council of Canada – Plant Biotechnology Institute." Botany 87, no. 6 (June 2009): 635–42. http://dx.doi.org/10.1139/b09-032.
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Limitations in the supply of the antimalarial compound artemisinin from Artemisia annua L. have led to an interest in understanding its biosynthesis and enhancing its production. Recent biochemical and molecular genetic data have implicated dihydroartemisinic aldehyde as a precursor to the corresponding acid, which is then converted to artemisinin. Thus, it is important to understand the enzyme or enzymes involved in dihydroartemisinic aldehyde oxidation. Given its activity on artemisinic aldehyde, the cytochrome P450 CYP71AV1 was investigated for its ability to oxidize dihydroartemisinic aldehyde. However, no net activity was detected. In a search for alternative enzymes that could catalyze the oxidation, an expressed sequence tag (EST) collection from A. annua was investigated for relevant cDNAs. This led to the isolation of a full-length cDNA encoding an aldehyde dehydrogenase homologue, named Aldh1, which is highly expressed in trichomes. Expression of the cDNA in E. coli and characterization of the purified recombinant enzyme revealed that the gene product catalyses the NAD(P)-dependent oxidation of the putative artemisinin precursors, artemisinic and dihydroartemsinic aldehydes, and a limited range of other aldehydes. The observed enzyme activity of Aldh1 and the expression pattern of the corresponding gene suggest a role in artemisinin biosynthesis in the glandular secretory trichomes of A. annua.
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Ullah, Najeeb, Hina Andaleeb, Celestin Nzanzu Mudogo, Sven Falke, Christian Betzel, and Carsten Wrenger. "Solution Structures and Dynamic Assembly of the 24-Meric Plasmodial Pdx1–Pdx2 Complex." International Journal of Molecular Sciences 21, no. 17 (August 19, 2020): 5971. http://dx.doi.org/10.3390/ijms21175971.
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Plasmodium species are protozoan parasites causing the deadly malaria disease. They have developed effective resistance mechanisms against most antimalarial medication, causing an urgent need to identify new antimalarial drug targets. Ideally, new drugs would be generated to specifically target the parasite with minimal or no toxicity to humans, requiring these drug targets to be distinctly different from the host’s metabolic processes or even absent in the host. In this context, the essential presence of vitamin B6 biosynthesis enzymes in Plasmodium, the pyridoxal phosphate (PLP) biosynthesis enzyme complex, and its absence in humans is recognized as a potential drug target. To characterize the PLP enzyme complex in terms of initial drug discovery investigations, we performed structural analysis of the Plasmodium vivax PLP synthase domain (Pdx1), glutaminase domain (Pdx2), and Pdx1–Pdx2 (Pdx) complex (PLP synthase complex) by utilizing complementary bioanalytical techniques, such as dynamic light scattering (DLS), X-ray solution scattering (SAXS), and electron microscopy (EM). Our investigations revealed a dodecameric Pdx1 and a monodispersed Pdx complex. Pdx2 was identified in monomeric and in different oligomeric states in solution. Interestingly, mixing oligomeric and polydisperse Pdx2 with dodecameric monodisperse Pdx1 resulted in a monodispersed Pdx complex. SAXS measurements revealed the low-resolution dodecameric structure of Pdx1, different oligomeric structures for Pdx2, and a ring-shaped dodecameric Pdx1 decorated with Pdx2, forming a heteromeric 24-meric Pdx complex.
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Komatsuya, Keisuke, Takaya Sakura, Kazuro Shiomi, Satoshi Ōmura, Kenji Hikosaka, Tomoyoshi Nozaki, Kiyoshi Kita, and Daniel Ken Inaoka. "Siccanin Is a Dual-Target Inhibitor of Plasmodium falciparum Mitochondrial Complex II and Complex III." Pharmaceuticals 15, no. 7 (July 21, 2022): 903. http://dx.doi.org/10.3390/ph15070903.
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Plasmodium falciparum contains several mitochondrial electron transport chain (ETC) dehydrogenases shuttling electrons from the respective substrates to the ubiquinone pool, from which electrons are consecutively transferred to complex III, complex IV, and finally to the molecular oxygen. The antimalarial drug atovaquone inhibits complex III and validates this parasite’s ETC as an attractive target for chemotherapy. Among the ETC dehydrogenases from P. falciparum, dihydroorotate dehydrogenase, an essential enzyme used in de novo pyrimidine biosynthesis, and complex III are the two enzymes that have been characterized and validated as drug targets in the blood-stage parasite, while complex II has been shown to be essential for parasite survival in the mosquito stage; therefore, these enzymes and complex II are considered candidate drug targets for blocking parasite transmission. In this study, we identified siccanin as the first (to our knowledge) nanomolar inhibitor of the P. falciparum complex II. Moreover, we demonstrated that siccanin also inhibits complex III in the low-micromolar range. Siccanin did not inhibit the corresponding complexes from mammalian mitochondria even at high concentrations. Siccanin inhibited the growth of P. falciparum with IC50 of 8.4 μM. However, the growth inhibition of the P. falciparum blood stage did not correlate with ETC inhibition, as demonstrated by lack of resistance to siccanin in the yDHODH-3D7 (EC50 = 10.26 μM) and Dd2-ELQ300 strains (EC50 = 18.70 μM), suggesting a third mechanism of action that is unrelated to mitochondrial ETC inhibition. Hence, siccanin has at least a dual mechanism of action, being the first potent and selective inhibitor of P. falciparum complexes II and III over mammalian enzymes and so is a potential candidate for the development of a new class of antimalarial drugs.
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STOCKS, P. A., V. BARTON, T. ANTOINE, G. A. BIAGINI, S. A. WARD, and P. M. O'NEILL. "Novel inhibitors of the Plasmodium falciparum electron transport chain." Parasitology 141, no. 1 (January 2014): 50–65. http://dx.doi.org/10.1017/s0031182013001571.
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SUMMARYDue to an increased need for new antimalarial chemotherapies that show potency against Plasmodium falciparum, researchers are targeting new processes within the parasite in an effort to circumvent or delay the onset of drug resistance. One such promising area for antimalarial drug development has been the parasite mitochondrial electron transport chain (ETC). Efforts have been focused on targeting key processes along the parasite ETC specifically the dihydroorotate dehydrogenase (DHOD) enzyme, the cytochrome bc1 enzyme and the NADH type II oxidoreductase (PfNDH2) pathway. This review summarizes the most recent efforts in antimalarial drug development reported in the literature and describes the evolution of these compounds.
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Forlemu, Neville Y., and Joseph Sloop. "Molecular dynamics simulations of the interactions between triose phosphate isomerase and sulfonamides." PeerJ Physical Chemistry 2 (September 3, 2020): e13. http://dx.doi.org/10.7717/peerj-pchem.13.
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Malaria is a disease with debilitating health and negative economic impacts in regions at high risk of infection. Parasitic resistance and side effects of current antimalarial drugs are major setbacks to the successful campaigns that have reduced malaria incidence by 40% in the last decade. The parasite’s dependence on glycolysis for energy requirements makes pathway enzymes suitable targets for drug development. Specifically, triose phosphate isomerase (TPI) from Plasmodium falciparum (pTPI) and human (hTPI) cells show striking structural features that can be used in development of new antimalarial agents. In this study MD simulations were used to characterize binding sites on hTPI and pTPI interactions with sulfonamides. The molecular mechanics Poisson–Boltzmann surface area (MM–PBSA) method was used to estimate the interaction energies of four sulfonamide-TPI docked complexes. A unique combination of key residues at the dimer interface of pTPI is responsible for the observed selective affinity to pTPI compared to hTPI. The representative sulfonamide; 4-amino-N-(3,5-dimethylphenyl)-3-fluorbenzenesulfonamide (sulfaE) shows a strong affinity with pTPI (dimer interface, −42.91 kJ/mol and active site region, −71.62 kJ/mol), hTPI (dimer interface, −41.32 kJ/mol and active site region, −84.40 kJ/mol). Strong and favorable Van der Waals interactions and increases in non-polar solvation energies explain the difference in affinity between pTPI with sulfaE compared to hTPI at the dimer interface. This is an indication that the dimer interface of TPI glycolytic enzyme is vital for development of sulfonamide based antimalarial drugs.
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Yousef, Bashir Alsiddig, Tanzeel Haider Elwaseela, Tagwa Abdalla Ali, Fatima Elamin Mohammed, Wala Osman Mohammed, Majdi Alobaid, and Amina Ibrahim Dirar. "Anti-malarial drugs as potential inhibitors of leishmania glycolytic enzymes: Development of new anti-leishmanial agents." Pharmacology and Clinical Pharmacy Research 5, no. 3 (December 2, 2020): 77. http://dx.doi.org/10.15416/pcpr.v5i3.29380.
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Leishmaniasis is one of the most important endemic diseases in Sudan. The glycolytic pathway is one of the essential pathways in the survival and pathogenicity of the leishmania parasite. This study aimed to evaluate the antileishmanial activities of three antimalarial drugs through targeting the glycolytic pathway inside the parasite. Antileishmanial activities of artesunate, quinine and mefloquine were evaluated using an in vitro anti-promastigote assay. Then, in silico molecular docking was conducted using Autodock 4.0 software to study the molecular interactions of antimalarial drugs to different key glycolytic enzymes. The results of the current study, Artesunate, quinine, and mefloquine showed effective inhibitory activities against L. donovani with IC50 values of 58.85, 40.24, and 20.06 μg/ml, respectively. Molecular docking analysis revealed interesting interactions between different antimalarial drugs and various glycolytic enzymes (Glucose-6-phosphate isomerase, Triosephosphate isomerase, Glycerol-3-phosphate dehydrogenase, Glyceraldehyde-3-phosphate dehydrogenase and Pyruvate kinase). Moreover, these drugs interact with different amino acid residues of the proteins with satisfactory binding energies, particularly with artesunate. According to binding energies, Glycerol-3-phosphate dehydrogenase was represented the most potential target for three tested drugs. Collectively, our results showed promising antileishmanial activities of different antimalarial that may mediated through inhibition of glycolysis process in leishmania donovani promastigote.
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Amir, Rhamal, Chaidir Chaidir, Aden Dhana Rizkita, and Anis Herliyanti. "ISOLASI DAN KARAKTERISASI EKSTRAK KULIT JENGKOL (Pithecellobium jiringa) SEBAGAI INHIBITOR ENZIM PENYAKIT MALARIA Plasmodium falciparum MALATE QUINONE OXIDOREDUCTASE." Jurnal Ilmu Farmasi dan Farmasi Klinik 19, no. 1 (June 30, 2022): 17. http://dx.doi.org/10.31942/jiffk.v19i1.6679.
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ABSTRACTIn order to discover and identify antimalarial active compounds, jengkol peel extract was isolated and tested for antimalarial activity. This study aims to determine the antimalarial active compound from jengkol peel extract which functions as an inhibitor of the Malate Quinone Oxidoreductase (MQO) enzyme. In this study, the extraction process was carried out using methanol as a solvent with the maceration method. The maceration results were then concentrated using a rotary evaporator with low pressure at a temperature of 40-45°C to obtain a Crude extract of 203 grams. Then liquid-liquid fractionation was carried out with four types of solvents, namely n-hexane, ethyl acetate, methanol, and water according to the level of polarity. Each fraction obtained was 400 ml which was then tested for enzyme inhibition using the MQO enzyme formation inhibition method. The fraction that had the highest inhibitory activity was the ethyl acetate fraction of 80%. Confirmation was done again with the same separation using column chromatography so as to produce the ethyl acetate fraction which was confirmed to be identified using HPLC producing peaks at retention times of 22 and 23 minutes. The results showed that in jengkol peel extract there were active compounds that acted as inhibitors of the MQO enzyme but further tests were needed to confirm these peak compounds.Keywords: antimalarial, HPLC, jengkol, matale quinone oxidoreductase
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Andrews, K. T., T. N. Tran, A. J. Lucke, P. Kahnberg, G. T. Le, G. M. Boyle, D. L. Gardiner, T. S. Skinner-Adams, and D. P. Fairlie. "Potent Antimalarial Activity of Histone Deacetylase Inhibitor Analogues." Antimicrobial Agents and Chemotherapy 52, no. 4 (January 22, 2008): 1454–61. http://dx.doi.org/10.1128/aac.00757-07.
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ABSTRACT The malaria parasite Plasmodium falciparum has at least five putative histone deacetylase (HDAC) enzymes, which have been proposed as new antimalarial drug targets and may play roles in regulating gene transcription, like the better-known and more intensively studied human HDACs (hHDACs). Fourteen new compounds derived from l-cysteine or 2-aminosuberic acid were designed to inhibit P. falciparum HDAC-1 (PfHDAC-1) based on homology modeling with human class I and class II HDAC enzymes. The compounds displayed highly potent antiproliferative activity against drug-resistant (Dd2) or drug sensitive (3D7) strains of P. falciparum in vitro (50% inhibitory concentration of 13 to 334 nM). Unlike known hHDAC inhibitors, some of these new compounds were significantly more toxic to P. falciparum parasites than to mammalian cells. The compounds inhibited P. falciparum growth in erythrocytes at both the early and late stages of the parasite's life cycle and caused altered histone acetylation patterns (hyperacetylation), which is a marker of HDAC inhibition in mammalian cells. These results support PfHDAC enzymes as being promising targets for new antimalarial drugs.
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Khan, Bushra Hasan, Shivangna Singh, Jameel Ahmad, and Farida Ahmad. "Covid-19: A Pharmacotherapeutic Perspective." Asian Journal of Pharmaceutical Research and Development 9, no. 1 (February 15, 2021): 183–89. http://dx.doi.org/10.22270/ajprd.v9i1.910.
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Introduction: COVID-19 disease has been difficult to tackle owing to the lack of typical therapeutic options. Many antivirals, antimalarial, and biologics are being carefully evaluated for treatment. This literature analysis aims to shed light to the ongoing studies concerning treatment possibilities for COVID-19 and assist as a reserve for health experts.
Objectives: This literature review was done to underline the efficacy and safety of existing treatment alternatives for COVID-19 and the cautious use of non-steroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.
Methods: PubMed, Medline, Embase and SCOPUS were meticulously browsed utilizing an amalgamation of the keywords "COVID 19," "SARS-CoV-2," and "treatment." All categories of articles together with clinical guidelines, case-studies and systematic reviews were assessed.
Conclusions: Treatments that unswervingly target SARS-CoV-2 are not present so far; however, several antivirals (Remdesivir) and antimalarials (Hydroxychloroquine) have appeared as valuable treatment possibilities. Remdesivir and convalescent plasma may be expected to play a beneficial role in serious patients with respiratory failure. Interleukin-6 (IL-6) antagonists could also be utilized in patients who progress and display evidence of cytokine release syndrome. Corticosteroids need to be avoided lest there is a gripping indication for their usage. Available evidence for prevention and treatment of COVID-19 must be utilized till recognized treatments are derived into reality.
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Jortzik, Esther, Boniface M. Mailu, Janina Preuss, Marina Fischer, Lars Bode, Stefan Rahlfs, and Katja Becker. "Glucose-6-phosphate dehydrogenase–6-phosphogluconolactonase: a unique bifunctional enzyme from Plasmodium falciparum." Biochemical Journal 436, no. 3 (May 27, 2011): 641–50. http://dx.doi.org/10.1042/bj20110170.
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The survival of malaria parasites in human RBCs (red blood cells) depends on the pentose phosphate pathway, both in Plasmodium falciparum and its human host. G6PD (glucose-6-phosphate dehydrogenase) deficiency, the most common human enzyme deficiency, leads to a lack of NADPH in erythrocytes, and protects from malaria. In P. falciparum, G6PD is combined with the second enzyme of the pentose phosphate pathway to create a unique bifunctional enzyme named GluPho (glucose-6-phosphate dehydrogenase–6-phosphogluconolactonase). In the present paper, we report for the first time the cloning, heterologous overexpression, purification and kinetic characterization of both enzymatic activities of full-length PfGluPho (P. falciparum GluPho), and demonstrate striking structural and functional differences with the human enzymes. Detailed kinetic analyses indicate that PfGluPho functions on the basis of a rapid equilibrium random Bi Bi mechanism, where the binding of the second substrate depends on the first substrate. We furthermore show that PfGluPho is inhibited by S-glutathionylation. The availability of recombinant PfGluPho and the major differences to hG6PD (human G6PD) facilitate studies on PfGluPho as an excellent drug target candidate in the search for new antimalarial drugs.
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Karpina, Veronika R., Svitlana S. Kovalenko, Sergiy M. Kovalenko, Oleksandr G. Drushlyak, Natalya D. Bunyatyan, Victoriya A. Georgiyants, Vladimir V. Ivanov, Thierry Langer, and Louis Maes. "A Novel Series of [1,2,4]Triazolo[4,3-a]Pyridine Sulfonamides as Potential Antimalarial Agents: In Silico Studies, Synthesis and In Vitro Evaluation." Molecules 25, no. 19 (September 30, 2020): 4485. http://dx.doi.org/10.3390/molecules25194485.
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For the development of new and potent antimalarial drugs, we designed the virtual library with three points of randomization of novel [1,2,4]triazolo[4,3-a]pyridines bearing a sulfonamide fragment. The library of 1561 compounds has been investigated by both virtual screening and molecular docking methods using falcipain-2 as a target enzyme. 25 chosen hits were synthesized and evaluated for their antimalarial activity in vitro against Plasmodium falciparum. 3-Ethyl-N-(3-fluorobenzyl)-N-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamide and 2-(3-chlorobenzyl)-8-(piperidin-1-ylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one showed in vitro good antimalarial activity with inhibitory concentration IC50 = 2.24 and 4.98 μM, respectively. This new series of compounds may serve as a starting point for future antimalarial drug discovery programs.
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Oliveira, Fabrício M., Luiz C. A. Barbosa, and Fyaz M. D. Ismail. "The diverse pharmacology and medicinal chemistry of phosphoramidates – a review." RSC Adv. 4, no. 36 (2014): 18998–9012. http://dx.doi.org/10.1039/c4ra01454e.
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Magnani, Giovanni, Michela Lomazzi, and Alessio Peracchi. "Completing the folate biosynthesis pathway in Plasmodium falciparum: p-aminobenzoate is produced by a highly divergent promiscuous aminodeoxychorismate lyase." Biochemical Journal 455, no. 2 (September 27, 2013): 149–55. http://dx.doi.org/10.1042/bj20130896.
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We identified the aminodeoxychorismate lyase from Plasmodium falciparum. This enzyme participates in the biosynthesis of folate and could be a new target for antimalarial therapy. The enzyme has little similarity to its bacterial counterparts and shows a minor D-amino acid transaminase activity.
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Duarte, Diana, and Nuno Vale. "How Antimalarials and Antineoplastic Drugs can Interact in Combination Therapies: A Perspective on the Role of PPT1 Enzyme." Current Drug Metabolism 22, no. 13 (November 2021): 1009–16. http://dx.doi.org/10.2174/1389200222666211118114057.
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: Antimalarial drugs from different classes have demonstrated anticancer effects in different types of cancer cells, but their complete mode of action in cancer remains unknown. Recently, several studies reported the important role of palmitoyl-protein thioesterase 1 (PPT1), a lysosomal enzyme, as the molecular target of chloroquine and its derivates in cancer. It was also found that PPT1 is overexpressed in different types of cancer, such as breast, colon, etc. Our group has found a synergistic interaction between antimalarial drugs, such as mefloquine, artesunate and chloroquine and antineoplastic drugs in breast cancer cells, but the mechanism of action was not determined. Here, we describe the importance of autophagy and lysosomal inhibitors in tumorigenesis and hypothesize that other antimalarial agents besides chloroquine could also interact with PPT1 and inhibit the mechanistic target of rapamycin (mTOR) signalling, an important pathway in cancer progression. We believe that PPT1 inhibition results in changes in the lysosomal metabolism that result in less accumulation of antineoplastic drugs in lysosomes, which increases the bioavailability of the antineoplastic agents. Taken together, these mechanisms help to explain the synergism of antimalarial and antineoplastic agents in cancer cells.
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Alam, Asrar, Md Kausar Neyaz, and Syed Ikramul Hasan. "Exploiting Unique Structural and Functional Properties of Malarial Glycolytic Enzymes for Antimalarial Drug Development." Malaria Research and Treatment 2014 (December 17, 2014): 1–13. http://dx.doi.org/10.1155/2014/451065.
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Metabolic enzymes have been known to carry out a variety of functions besides their normal housekeeping roles known as “moonlighting functions.” These functionalities arise from structural changes induced by posttranslational modifications and/or binding of interacting proteins. Glycolysis is the sole source of energy generation for malaria parasite Plasmodium falciparum, hence a potential pathway for therapeutic intervention. Crystal structures of several P. falciparum glycolytic enzymes have been solved, revealing that they exhibit unique structural differences from the respective host enzymes, which could be exploited for their selective targeting. In addition, these enzymes carry out many parasite-specific functions, which could be of potential interest to control parasite development and transmission. This review focuses on the moonlighting functions of P. falciparum glycolytic enzymes and unique structural differences and functional features of the parasite enzymes, which could be exploited for therapeutic and transmission blocking interventions against malaria.
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Tegar Achsendo, Yuniarta, Wawo Jesica Ersty, and Kesuma Dini. "MOLECULAR DOCKING STUDY OF 1‑(PYRIDIN-4-YL)PYRROLIDINE-2-ONE DERIVATE AGAINST PROLYL-tRNA SYNTHETASE IN PLASMODIUM FALCIPARUM." Pharmacoscript 5, no. 2 (August 31, 2022): 157–71. http://dx.doi.org/10.36423/pharmacoscript.v5i2.1003.
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Prolyl-tRNA synthetase is one of the novel targets to develop antimalarial drug candidate. Several class of inhibitors have been identified for the enzyme, one of which is pyridine-pyrrolidinone derivative. It is recently known that 4‐[3‐cyano‐3‐(1‐methylcyclopropyl)‐2‐oxopyrrolidin‐1‐yl]‐N‐{[3‐fluoro‐5‐(1‐methyl‐1H‐pyrazol‐4‐yl)phenyl]methyl}‐6‐methylpyridine‐2‐carboxamide possess potent antimalarial activity, possibly via prolyl-tRNA synthetase inhibition. This compound possesses two enantiomeric form which yielded antimalarial bioactivity in different magnitude. It is argued that this compound occupies ATP binding site. However, 3D structure of ligand-protein complex has yet to be elucidated. This study aimed to predict binding mode and affinity of two enantiomers of 4‐[3‐cyano‐3‐(1‐methylcyclopropyl)‐2‐oxopyrrolidin‐1‐yl]‐N‐{[3‐fluoro‐5‐(1‐methyl‐1H‐pyrazol‐4‐yl)phenyl]methyl}‐6‐methylpyridine‐2‐carboxamide using molecular docking approach with EasyDockVina 2.2. The results showed that S enantiomer possess better ligand affinity (-0.81±3.98) compared to R enantiomer (1.74±2.71). The result was in line with in vitro antimalarial assay, which stated the potency of S enantiomer more than R enantiomer. In addition, it is argued that residue GLN475 and THR478 plays important role in ligand-enzyme interaction. Further studies are needed to verify the result with more robust in silico method and enzymatic bioassay.
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Verma, P., B. Chauhan, R. Singh, A. K. Gupta, and D. Rani. "In silico study, Synthesis and evaluation purine analogues as potential antimalarial agents." Research Journal of Chemistry and Environment 26, no. 7 (June 25, 2022): 77–84. http://dx.doi.org/10.25303/2607rjce077084.
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The challenges concerning the control of malaria remain due to the continuous emergence of drug resistant strains. Available treatments for this disease present several limitations such as lack of efficacy, toxic side effects and drug resistance. One of the most striking differences was found in the purine metabolism, because parasites are incapable of de novo purine biosynthesis in which enzyme HGPRT is central to the purine salvage pathway and whose activity is critical for the production of the nucleotides required for DNA/RNA synthesis within this protozoan parasite. Thus, new drugs are urgently needed. Herein we have designed, docked, synthesized and screened 9-alkyl purine derivatives for antimalarial activity against pfHGPRT. We have reported four compounds with promising activity against the highly artimisnin resistant P. falciparum namely: compounds 2,6-dichloro-9-(propan-2-yl)-9H-purine (1a), 9-Butyl-2,6-dichloro-9H-purine (1b), 2,6-dichloro-9-(2-methylbutyl)-9H-purine (1c), 2,6-dichloro-9-pentyl-9H-purine (1d) and binding energies to predictable antimalarial agents (-5.1, -5.3, -5.5 and -5.6 kcal/mole and rmsd 1.198, 1.238, 1.354 and 1.554 respectively). These analogs have acceptable binding interactions, Moreover, an in silico docking study revealed that P. falciparum and hypoxanthine guanine phosphoribosyltransferase enzymes could be the potential targets of those compounds. Our study identified novel, purine-based chemotypes that could be further optimized to generate potent and diversified anti-parasitic drugs against malaria.
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Bhunya, Rajabrata, Suman Nandy, and Alpana Seal. "An in silico structural insights into Plasmodium LytB protein and its inhibition." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C1791. http://dx.doi.org/10.1107/s2053273314082096.
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In most of the pathogenic organisms including Plasmodium falciparum, isoprenoids are synthesized via MEP (MethylErythritol 4-Phosphate) pathway. LytB is the last enzyme of this pathway which catalyzes the conversion of (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate (HMBPP) into the two isoprenoid precursors: isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Since the MEP pathway is not used by humans, it represents an attractive target for the development of new antimalarial compounds or inhibitors. Here a systematic in-silico study has been conducted to get an insight into the structure of Plasmodium lytB as well as its affinities towards different inhibitors. We used comparative modeling technique to predict the three dimensional (3D) structure of Plasmodium LytB taking E. Coli LytB protein (PDB ID: 3KE8) as template and the model was subsequently refined through molecular dynamics (MD) simulation. A large ligand dataset containing diphospate group was subjected for virtual screening against the target using GOLD 5.2 program. Considering the mode of binding and affinities, 17 leads were selected on basis of binding energies in comparison to its substrate HMBPP (Gold.Chemscore.DG: -20.9734 kcal/mol). Among them, 5 were discarded because of their inhibitory activity towards other human enzymes. The rest 12 potential leads carry all the properties of any "drug like" molecule and the knowledge of Plasmodium LytB inhibitory mechanism which can provide valuable support for the antimalarial inhibitor design in future.
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Mishra, Richa, Brijeshkunvar Mishra ., and N. S. Hari Narayana M. . "Dihydrofolate Reductase Enzyme: A Potent Target for Antimalarial Research." Asian Journal of Cell Biology 1, no. 1 (December 15, 2005): 48–58. http://dx.doi.org/10.3923/ajcb.2006.48.58.
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Holland, Zoë, Renaud Prudent, Jean-Baptiste Reiser, Claude Cochet, and Christian Doerig. "Functional Analysis of Protein Kinase CK2 of the Human Malaria Parasite Plasmodium falciparum." Eukaryotic Cell 8, no. 3 (December 29, 2008): 388–97. http://dx.doi.org/10.1128/ec.00334-08.
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ABSTRACT Protein kinase CK2 (casein kinase 2) is a eukaryotic serine/threonine protein kinase with multiple substrates and roles in diverse cellular processes, including differentiation, proliferation, and translation. The mammalian holoenzyme consists of two catalytic alpha or alpha′ subunits and two regulatory beta subunits. We report the identification and characterization of a Plasmodium falciparum CK2α orthologue, PfCK2α, and two PfCK2β orthologues, PfCK2β1 and PfCK2β2. Recombinant PfCK2α possesses protein kinase activity, exhibits similar substrate and cosubstrate preferences to those of CK2α subunits from other organisms, and interacts with both of the PfCK2β subunits in vitro. Gene disruption experiments show that the presence of PfCK2α is crucial to asexual blood stage parasites and thereby validate the enzyme as a possible drug target. PfCK2α is amenable to inhibitor screening, and we report differential susceptibility between the human and P. falciparum CK2α enzymes to a small molecule inhibitor. Taken together, our data identify PfCK2α as a potential target for antimalarial chemotherapeutic intervention.
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Musyoka, Thommas, and Özlem Tastan Bishop. "South African Abietane Diterpenoids and Their Analogs as Potential Antimalarials: Novel Insights from Hybrid Computational Approaches." Molecules 24, no. 22 (November 7, 2019): 4036. http://dx.doi.org/10.3390/molecules24224036.
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The hemoglobin degradation process in Plasmodium parasites is vital for nutrient acquisition required for their growth and proliferation. In P. falciparum, falcipains (FP-2 and FP-3) are the major hemoglobinases, and remain attractive antimalarial drug targets. Other Plasmodium species also possess highly homologous proteins to FP-2 and FP-3. Although several inhibitors have been designed against these proteins, none has been commercialized due to associated toxicity on human cathepsins (Cat-K, Cat-L and Cat-S). Despite the two enzyme groups sharing a common structural fold and catalytic mechanism, distinct active site variations have been identified, and can be exploited for drug development. Here, we utilize in silico approaches to screen 628 compounds from the South African natural sources to identify potential hits that can selectively inhibit the plasmodial proteases. Using docking studies, seven abietane diterpenoids, binding strongly to the plasmodial proteases, and three additional analogs from PubChem were identified. Important residues involved in ligand stabilization were identified for all potential hits through binding pose analysis and their energetic contribution determined by binding free energy calculations. The identified compounds present important scaffolds that could be further developed as plasmodial protease inhibitors. Previous laboratory assays showed the effect of the seven diterpenoids as antimalarials. Here, for the first time, we demonstrate that their possible mechanism of action could be by interacting with falcipains and their plasmodial homologs. Dynamic residue network (DRN) analysis on the plasmodial proteases identified functionally important residues, including a region with high betweenness centrality, which had previously been proposed as a potential allosteric site in FP-2.
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Choubey, Vinay, Pallab Maity, Mithu Guha, Sanjay Kumar, Kumkum Srivastava, Sunil Kumar Puri, and Uday Bandyopadhyay. "Inhibition of Plasmodium falciparum Choline Kinase by Hexadecyltrimethylammonium Bromide: a Possible Antimalarial Mechanism." Antimicrobial Agents and Chemotherapy 51, no. 2 (December 4, 2006): 696–706. http://dx.doi.org/10.1128/aac.00919-06.
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ABSTRACT Choline kinase is the first enzyme in the Kennedy pathway (CDP-choline pathway) for the biosynthesis of the most essential phospholipid, phosphatidylcholine, in Plasmodium falciparum. In addition, choline kinase also plays a pivotal role in trapping essential polar head group choline inside the malaria parasite. Recently, Plasmodium falciparum choline kinase (PfCK) has been cloned, overexpressed, and purified. However, the function of this enzyme in parasite growth and survival has not been evaluated owing to the lack of a suitable inhibitor. Purified recombinant PfCK enabled us to identify an inhibitor of PfCK, hexadecyltrimethylammonium bromide (HDTAB), which has a very close structural resemblance to hexadecylphosphocholine (miltefosin), the well-known antiproliferative and antileishmanial drug. HDTAB inhibited PfCK in a dose-dependent manner and offered very potent antimalarial activity in vitro against Plasmodium falciparum. Moreover, HDTAB exhibited profound antimalarial activity in vivo against the rodent malaria parasite Plasmodium yoelii (N-67 strain). Interestingly, parasites at the trophozoite and schizont stages were found to be particularly sensitive to HDTAB. The stage-specific antimalarial effect of HDTAB correlated well with the expression pattern of PfCK in P. falciparum, which was observed by reverse transcription-PCR and immunofluorescence microscopy. Furthermore, the antimalarial activity of HDTAB paralleled the decrease in phosphatidylcholine content, which was found to correlate with the decreased phosphocholine generation. These results suggest that inhibition of choline kinase by HDTAB leads to decreased phosphocholine, which in turn causes a decrease in phosphatidylcholine biosynthesis, resulting in death of the parasite.
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Chinnappanna, Naveen Kumar Reddy, Gopi Yennam, Chaitanya Budagam Haima Naga Venkata Chaitanya, Shinu Pottathil, Pobitra Borah, Katharigatta N. Venugopala, Pran Kishore Deb, and Raghu Prasad Mailavaram. "Recent approaches in the drug research and development of novel antimalarial drugs with new targets." Acta Pharmaceutica 73, no. 1 (January 24, 2023): 1–27. http://dx.doi.org/10.2478/acph-2023-0001.
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Abstract Malaria is a serious worldwide medical issue that results in substantial annual death and morbidity. The availability of treatment alternatives is limited, and the rise of resistant parasite types has posed a significant challenge to malaria treatment. To prevent a public health disaster, novel antimalarial agents with single-dosage therapies, extensive curative capability, and new mechanisms are urgently needed. There are several approaches to developing antimalarial drugs, ranging from alterations of current drugs to the creation of new compounds with specific targeting abilities. The availability of multiple genomic techniques, as well as recent advancements in parasite biology, provides a varied collection of possible targets for the development of novel treatments. A number of promising pharmacological interference targets have been uncovered in modern times. As a result, our review concentrates on the most current scientific and technical progress in the innovation of new antimalarial medications. The protein kinases, choline transport inhibitors, dihydroorotate dehydrogenase inhibitors, isoprenoid biosynthesis inhibitors, and enzymes involved in the metabolism of lipids and replication of deoxyribonucleic acid, are among the most fascinating antimalarial target proteins presently being investigated. The new cellular targets and drugs which can inhibit malaria and their development techniques are summarised in this study.
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Kapelski, Stephanie, Melanie de Almeida, Rainer Fischer, Stefan Barth, and Rolf Fendel. "Antimalarial Activity of Granzyme B and Its Targeted Delivery by a Granzyme B–Single-Chain Fv Fusion Protein." Antimicrobial Agents and Chemotherapy 59, no. 1 (October 13, 2014): 669–72. http://dx.doi.org/10.1128/aac.04190-14.
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ABSTRACTWe present here the first evidence that granzyme B acts againstPlasmodium falciparum(50% inhibitory concentration [IC50], 1,590 nM; 95% confidence interval [95% CI], 1,197 to 2,112 nM). We created a novel antimalarial fusion protein consisting of granzyme B fused to a merozoite surface protein 4 (MSP4)-specific single-chain Fv protein (scFv), which targets the enzyme to infected erythrocytes, with up to an 8-fold reduction in the IC50(176 nM; 95% CI, 154 to 202 nM). This study confirms the therapeutic efficacies of recombinant antibody-mediated antimalarial immunotherapeutics based on granzyme B.
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Asimus, Sara, Doaa Elsherbiny, Trinh N. Hai, Britt Jansson, Nguyen V. Huong, Max G. Petzold, Ulrika S. H. Simonsson, and Michael Ashton. "Artemisinin antimalarials moderately affect cytochrome P450 enzyme activity in healthy subjects." Fundamental & Clinical Pharmacology 21, no. 3 (June 2007): 307–16. http://dx.doi.org/10.1111/j.1472-8206.2007.00471.x.
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