Academic literature on the topic 'Enzymes - Antimalarials'
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Journal articles on the topic "Enzymes - Antimalarials"
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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.
Dissertations / Theses on the topic "Enzymes - Antimalarials"
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Njuguna, Joyce Njoki. "Structural analysis of prodomain inhibition of cysteine proteases in plasmodium species." Thesis, Rhodes University, 2012. http://hdl.handle.net/10962/d1004081.
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Plasmodium is a genus of parasites causing malaria, a virulent protozoan infection in humans resulting in over a million deaths annually. Treatment of malaria is increasingly limited by parasite resistance to available drugs. Hence, there is a need to identify new drug targets and authenticate antimalarial compounds that act on these targets. A relatively new therapeutic approach targets proteolytic enzymes responsible for parasite‟s invasion, rupture and hemoglobin degradation at the erythrocytic stage of infection. Cysteine proteases (CPs) are essential for these crucial roles in the intraerythrocytic parasite. CPs are a diverse group of enzymes subdivided into clans and further subdivided into families. Our interest is in Clan CA, papain family C1 proteases, whose members play numerous roles in human and parasitic metabolism. These proteases are produced as zymogens having an N-terminal extension known as the prodomain which regulates the protease activity by selectively inhibiting its active site, preventing substrate access. A Clan CA protease Falcipain-2 (FP-2) of Plasmodium falciparum is a validated drug target but little is known of its orthologs in other malarial Plasmodium species. This study uses various structural bioinformatics approaches to characterise the prodomain‟s regulatory effect in FP-2 and its orthologs in Plasmodium species (P. vivax, P. berghei, P. knowlesi, P. ovale, P. chabaudi and P. yoelii). This was in an effort to discover short peptides with essential residues to mimic the prodomain‟s inhibition of these proteases, as potential peptidomimetic therapeutic agents. Residues in the prodomain region that spans over the active site are most likely to interact with the subsite residues inhibiting the protease. Sequence analysis revealed conservation of residues in this region of Plasmodium proteases that differed significantly in human proteases. Further prediction of the 3D structure of these proteases by homology modelling allowed visualisation of these interactions revealing differences between parasite and human proteases which will lead to significant contribution in structure based malarial inhibitor design.
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Mokoena, Fortunate. "Malarial drug targets cysteine proteases as hemoglobinases." Thesis, Rhodes University, 2012. http://hdl.handle.net/10962/d1004065.
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Malaria has consistently been rated as the worst parasitic disease in the world. This disease affects an estimated 5 billion households annually. Malaria has a high mortality rate leading to distorted socio-economic development of the world at large. The major challenge pertaining to malaria is its continuous and rapid spread together with the emergence of drug resistance in Plasmodium species (vector agent of the disease). For this reason, researchers throughout the world are following new leads for possible drug targets and therefore, investigating ways of curbing the spread of the disease. Cysteine proteases have emerged as potential antimalarial chemotherapeutic targets. These particular proteases are found in all living organisms, Plasmodium cysteine proteases are known to degrade host hemoglobin during the life cycle of the parasite within the human host. The main objective of this study was to use various in silico methods to analyze the hemoglobinase function of cysteine proteases in P. falciparum and P. vivax. Falcipain-2 (FP2) of P. falciparum is the best characterized of these enzymes, it is a validated drug target. Both the three-dimensional structures of FP2 and its close homologue falcipain-3 (FP3) have been solved by the experimental technique X-ray crystallography. However, the homologue falcipain-2 (FP2’)’ and orthologues from P.vivax vivapain-2 (VP2) and vivapain-3 (VP3) have yet to be elucidated by experimental techniques. In an effort to achieve the principal goal of the study, homology models of the protein structures not already elucidated by experimental methods (FP2’, VP2 and VP3) were calculated using the well known spatial restraint program MODELLER. The derived models, FP2 and FP3 were docked to hemoglobin (their natural substrate). The protein-protein docking was done using the unbound docking program ZDOCK. The substrate-enzyme interactions were analyzed and amino acids involved in binding were observed. It is anticipated that the results obtained from the study will help focus inhibitor design for potential drugs against malaria. The residues found in both the P. falciparum and P. vivax cysteine proteases involved in hemoglobin binding have been identified and some of these are proposed to be the main focus for the design of a peptidomimetric inhibitor.
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Silva, Márcia Ferreira da. "Estudos in vitro de potenciais antimaláricos nos estágios intraeritrocítico de Plasmodium falciparum." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/42/42135/tde-23042013-122652/.
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Nesta dissertação, identificou-se que as drogas esqualestatina, fosmidomicina, risedronato e nerolidol apresentam atividades sinérgicas e aditivas quando administradas em cultura de P. falciparum. Esses resultados contribuem para a compreensão da biologia do parasita e abrem estudos para possíveis antimaláricos. Identificou-se a especificidade da droga esqualestatina inibidora da enzima fitoeno sintase por meio de marcações metabólicas utilizando precursor radioativo ([3H]GGPP), e análise pela técnica de cromatografia (RP-HPLC). Realizou-se testes de inibição para determinar o valor da IC50 na linhagem pRM2-Fito-HA, a qual encontra-se super expressando enzima fitoeno sintase e encontrou-se um valor IC50 de 5 mM para o isolado 3D7 enquanto que para a linhagem pRM2-Fito-HA foi de 30 mM. Demonstrando assim que a enzima fitoeno sintase é o principal, senão único alvo da esqualestatina em P. falciparum, o que sugere que este composto ou derivado do mesmo são potenciais antimalaricos.In this thesis, we found that the drug squalestatin, fosmidomicina, risedronate, nerolidol have synergistic and additive activity when administered in cultured P. falciparum. These results contribute to the understanding of the biology of the parasite and open studies for potential antimalarials. We identified the specific drug squalestatin inhibiting phytoene synthase enzyme by using metabolic markers radioactive precursor ([3H] GGPP) by the technique of analysis and chromatography (RP-HPLC). Held inhibition tests to determine the IC50 value of the strain in pRM2-Phyto-HA, which is super expressing phytoene synthase enzyme and met an IC50 value of 5 microM to isolate 3D7 whereas for strain pRM2 -Phyto-HA was 30 mM. Thus demonstrating that the enzyme phytoene synthase is the primary, if not sole target of squalestatin in P. falciparum, which suggests that this compound or derivative thereof as potential antimalarials.
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Thirumalairajan, Srinath. "Design and synthesis of enzyme inhibitors as potential antibacterials and antimalarials." Thesis, University of Leeds, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417729.
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Tran, Thanh Nguyen. "Plasmodium Falciparum Histone Deacetylases as Novel Antimalarial Drug Targets." Thesis, Griffith University, 2010. http://hdl.handle.net/10072/367456.
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Histone deacetylases (HDACs) are recognised as potential drug targets for many diseases including
cancer, inflammatory diseases and some parasitic diseases including malaria. In eukaryotic cells,
these enzymes play an important role in transcriptional regulation through modification of
chromatin structure. Inhibitors of mammalian HDAC enzymes including trichostain A and apicidin
are active against P. falciparum parasites, however these compounds are not selective for malaria
parasites versus normal cell lines. The aims of this study were to examine the antimalarial potential
of new hydroxamate-based HDAC inhibitors and to investigate a P. falciparum HDAC, PfHDAC1,
as a potential new antimalarial drug target.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Health Science
Griffith Health
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Turgut, Dilek. "Overproduction of the active lactate dehydrogenase from Plasmodium falciparum opens a route to obtain new antimalarials." Thesis, University of Bristol, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389088.
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Yao, Jia. "Synthesis of silver nanoparticles and their role against a thiazolekinase enzyme from Plasmodium falciparum." Thesis, Rhodes University, 2014. http://hdl.handle.net/10962/d1020894.
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Malaria, a mosquito-borne infectious disease, caused by the protozoan Plasmodium genus, is the greatest health challenges worldwide. The plasmodial vitamin B1 biosynthetic enzyme PfThzK diverges significantly, both structurally and functionally from its counterpart in higher eukaryotes, thereby making it particularly attractive as a biomedical target. In the present study, PfThzK was recombinantly produced as 6×His fusion protein in E. coli BL21, purified using nickel affinity chromatography and size exclusion chromatography resulting in 1.03% yield and specific activity 0.28 U/mg. The enzyme was found to be a monomer with a molecular mass of 34 kDa. Characterization of the PfThzK showed an optimum temperature and pH of 37°C and 7.5 respectively, and it is relatively stable (t₁/₂=2.66 h). Ag nanoparticles were synthesized by NaBH₄/tannic acid, and characterized by UV-vis spectroscopy and transmission electron microscopy. The morphologies of these Ag nanoparticles (in terms of size) synthesized by tannic acid appeared to be more controlled with the size of 7.06±2.41 nm, compared with those synthesized by NaBH₄, with the sized of 12.9±4.21 nm. The purified PfThzK was challenged with Ag NPs synthesized by tannic acid, and the results suggested that they competitively inhibited PfThzK (89 %) at low concentrations (5-10 μM) with a Ki = 6.45 μM.
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Cao, Yu. "The synthesis of organo-phosphorus transition-state analogue inhibitors of dihydroorotase." Master's thesis, Canberra, ACT : The Australian National University, 1994. http://hdl.handle.net/1885/141358.
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Baumgartner, Corinne. "Strukturbasiertes Design und Synthese von Inhibitoren des Enzyms IspF als potentielle Antimalaria-Wirkstoffe /." Zürich : ETH, 2007. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=17402.
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Conibear, Anne Claire. "Synthesis and evaluation of novel inhibitors of 1-Deoxy-D-xylolose-5-phosphate reductoisomerase as potential antimalarials." Thesis, Rhodes University, 2013. http://hdl.handle.net/10962/d1008282.
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Malaria continues to be an enormous health-threat in the developing world and the emergence of drug resistance has further compounded the problem. The parasite-specific enzyme, 1-deoxY-D-xylulose-S-phosphate reductoisomerase (DXR), has recently been validated as a promising antimalarial drug target. The present study comprises a combination of synthetic, physical organic, computer modelling and bioassay techniques directed towards the development of novel DXR inhibitors. A range of 2-heteroarylamino-2-oxoethyl- and 2- heteroarylamino-2-oxopropyl phosphonate esters and their corresponding phosphonic acid salts have been synthesised as analogues of the highly active DXR inhibitor, fosmidomycin. Treatment of the heteroarylamino precursors with chloroacetyl chloride or chloropropionyl chloride afforded chloroamide intermediates, Arbuzov reactions of which led to the corresponding diethyl phosphonate esters. Hydrolysis of the esters has been effected using bromotrimethylsilane. Twenty-four new compounds have been prepared and fully characterised using elemental (HRMS or combustion) and spectroscopic (1- and 2-D NMR and IR) analysis. A 31p NMR kinetic study has been carried out on the two-step silylation reaction involved in the hydrolysis of the phosphonate esters and has provided activation parameters for the reaction. The kinetic analysis was refined using a computational method to give an improved fit with the experimental data. Saturation transfer difference (STD) NMR analysis, computer-simulated docking and enzyme inhibition assays have been used to evaluate the enzyme-binding and -inhibition potential of the synthesised ligands. Minimal to moderate inhibitory activity has been observed and several structure-activity relationships have been identified. In silica exploration of the DXR active site has revealed an additional binding pocket and information on the topology of the active site has led to the de novo design of a new series of potential ligands.KMBT_363
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Book chapters on the topic "Enzymes - Antimalarials"
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V.T. Minnow, Yacoba, and Vern L. Schramm. "Purine and Pyrimidine Pathways as Antimalarial Targets." In Malaria - Recent Advances, and New Perspectives [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.106468.
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Malaria continues to plague the endemic regions of sub-Saharan Africa and Southeast Asia. With the current development of artemisinin resistance and a risk of failure of the current first line therapies, there is a growing need for novel antimalarials. Purine and pyrimidine metabolism in Plasmodium is distinctly different from the human host, making these pathways valid targets for the development of novel antimalarials. Targeting key enzymes in these pathways with transition state analogs has provided high affinity inhibitors. Transition state mimicry can also provide selectivity for the parasite enzymes over the homologous enzymes of the human host. Resistance of Plasmodium parasites to current antimalarials will be compared to resistance development induced by transition state analogs inhibitors, a feature that may contribute to decreased resistance development. Tight binding and specificity of transition state analog inhibitors provide important features for novel antimalaria therapy with low toxicity and prevention of antibiotic resistance.
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Luzzatto, Lucio. "Glucose-6-phosphate dehydrogenase deficiency." In Oxford Textbook of Medicine, edited by Chris Hatton and Deborah Hay, 5472–79. Oxford University Press, 2020. http://dx.doi.org/10.1093/med/9780198746690.003.0541.
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Deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD) in red blood cells is an inherited abnormality due to mutations of the G6PD gene on the X chromosome that renders the cells vulnerable to oxidative damage. The condition is widespread in many populations living in or originating from tropical and subtropical areas of the world because it confers a selective advantage against Plasmodium falciparum malaria. Clinical features—G6PD deficiency is mostly an asymptomatic trait, but it predisposes to acute haemolytic anaemia in response to exogenous triggers, including (1) ingestion of fava beans—favism; (2) certain bacterial and viral infections; and (3) some drugs—notably some antimalarials (e.g. primaquine), some antibiotics (e.g. sulphanilamide, dapsone, nitrofurantoin), and even aspirin in high doses. Other manifestations include (1) severe neonatal jaundice; and (2) chronic nonspherocytic haemolytic anaemia—the latter is only seen with rare specific genetic variants. The acute haemolytic attack typically starts with malaise, weakness, and abdominal or lumbar pain, followed by the development of jaundice and passage of dark urine (haemoglobinuria). Most episodes resolve spontaneously. Diagnosis relies on the direct demonstration of decreased activity of G6PD in red cells: a variety of screening tests are available, with (ideally) subsequent confirmation by quantitative assay. Prevention is by avoiding exposure to triggering factors of previously screened subjects. Prompt blood transfusion is indicated in severe acute haemolytic anaemia and may be life-saving.
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Taber, Douglass F. "Alkaloid Synthesis: Indolizidine 223AB (Cha), Lepadiformine (Kim), Kainic Acid (Fukuyama), Gephyrotoxin (Smith), Premarineosin A (Reynolds)." In Organic Synthesis. Oxford University Press, 2017. http://dx.doi.org/10.1093/oso/9780190646165.003.0059.
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Jin Kun Cha of Wayne State University prepared (Org. Lett. 2014, 16, 6208) the allene 1 by SN2′ coupling of a cyclopropanol with a propargylic tosylate. Silver-mediated cyclization converted 1 into 2, that was reduced with diimide to the Dendrobates alkaloid indolizidine 223AB 3. Sanghee Kim of Seoul National University observed (Chem. Eur. J. 2014, 20, 17433) high diastereoselectivity in the Ireland–Claisen rearrangement of 4 to 5. The acid 5 was the key intermediate for the synthesis of the tunicate alkaloid lepadiformine 6. Tohru Fukuyama of Nagoya University also used (Eur. J. Org. Chem. 2014, 4823) an ester enolate Claisen rearrangement to set the relative and absolute configuration of 7. Pd-catalyzed cyclization then led to 8, that was carried on to the excitatory amino acid receptor agonist kainic acid 9. Gephyrotoxin 12 was so named because it incorporates structural elements from two different classes of the Dendrobates alkaloids. Martin D. Smith of the University of Oxford envisioned (Angew. Chem. Int. Ed. 2014, 53, 13826) the cascade cyclization of deprotected 10 to give, after reduction, the ketone 11. Zhen Yang of the Peking University Shenzhen Graduate School showed (Chem. Eur. J. 2014, 20, 12881) that the Rh carbene derived from 13 readily cyclized to an imine. The facial selectivity of the addition of the Grignard reagent 14 to that imine depended on the temperature of the reaction. At room temperature, 15 was formed. At low temperature, the other diastereomer predominated. Ring-closing metathesis was used for the elaboration of 15 to the Stemona alkaloid tuberostemospiroline 16. Kevin A. Reynolds of Portland State University prepared (J. Org. Chem. 2014, 79, 11674) 19 by condensation of the pyrrole 17 with the aldehyde 18. The biosynthetic enzyme, that they had overexpressed, oxidized 19 to the antimalarial alkaloid permarineosin A 20.
Conference papers on the topic "Enzymes - Antimalarials"
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"Virtual Screening the Interaction of Various Compound from Indonesian Plants with the HGXPRT Enzyme to Find a Novel Antimalarial Drug." In The 3rd International Conference on Life Sciences and Biotechnology. Galaxy Science, 2021. http://dx.doi.org/10.11594/nstp.2021.0805.
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