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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malaria, one of the major reemerging parasitic diseases, is caused by protozoal parasites belonging to the genus plasmodia. Antimalarial drugs have played a mainstream role in controlling the spread of malaria through the treatment of patients infected with the plasmodial parasites and controlling its transmissibility. The current line of therapy against malaria is faced with the hurdles of a low or total lack of efficacy due to the evolution of drug-resistant strains of the malarial parasites. Preventive vaccination against malaria is an ideal solution to this problem but is not expected to arrive for at least a decade. Development of antimalarial drugs involving novel mechanisms of action is therefore of imminent importance. Several novel drug candidates of synthetic and natural products origin as well as their combination therapies are currently being evaluated for their efficacy against the drug-resistant strains of the parasites. Various plasmodial targets/pathways, such as the Purine salvage pathway, Pyrimidine biosynthesis pathway as well as the processes in the apicoplast, have been identified and are being utilized for the discovery and development of novel antimalarial therapies. This review provides an overview of the latest developments in terms of drugs, combination therapies and novel plasmodial targets being carried out to counter the menace of drug-resistant malaria.
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PMID:The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. 1822 Jul 71

A library of aromatic/heterocyclic sulfonamides possessing a large diversity of scaffolds has been assayed for inhibition of the carbonic anhydrase (CA, EC 4.2.1.1) from the malaria parasite Plasmodium falciparum (pfCA). Low micromolar and submicromolar in vitro inhibitors were detected, whereas several compounds showed ex vivo anti-P. falciparum activity, in cell cultures. One derivative, that is, 4-(3,4-dichlorophenylureido)thioureido-benzenesulfonamide was an effective in vitro pfCA inhibitor (K(I) of 0.18 microM), inhibited the ex vivo growth of P. falciparum with an IC(50) of 1 microM, and was also effective as an antimalarial agent in mice infected with P. berghei, an animal model of human malaria infection, with an ID(50) of 10 mg/kg (chloroquine as standard showed an ID(50) of 5 mg/kg). By inhibiting the first step of pyrimidine nucleotide biosyntheses, that is, the CA-mediated carbamoylphosphate biosynthesis, sulfonamide inhibitors of the protozoan CAs may have potential for the development of novel therapies of human malaria.
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PMID:Carbonic anhydrase inhibitors: inhibition of Plasmodium falciparum carbonic anhydrase with aromatic/heterocyclic sulfonamides-in vitro and in vivo studies. 1880 93

The thymine-uracil exchange constitutes one of the major chemical differences between DNA and RNA. Although these two bases form the same Watson-Crick base pairs with adenine and are equivalent for both information storage and transmission, uracil incorporation in DNA is usually a mistake that needs to be excised. There are two ways for uracil to appear in DNA: thymine replacement and cytosine deamination. Most DNA polymerases readily incorporate dUMP as well as dTMP depending solely on the availability of the d(U/T)TP building block nucleotides. Cytosine deamination results in mutagenic U:G mismatches that must be excised. The repair system, however, also excises U from U:A "normal" pairs. It is therefore crucial to limit thymine-replacing uracils.dUTP is constantly produced in the pyrimidine biosynthesis network. To prevent uracil incorporation into DNA, representatives of the dUTP nucleotidohydrolase (dUTPase) enzyme family eliminate excess dUTP. This Account describes recent studies that have provided important detailed insights into the structure and function of these essential enzymes.dUTPases typically possess exquisite specificity and display an intriguing homotrimer active site architecture. Conserved residues from all three monomers contribute to each of the three active sites within the dUTPase. Although even dUTPases from evolutionarily distant species possess similar structural and functional traits, in a few cases, a monomer dUTPase mimics the trimer structure through an unusual folding pattern. Catalysis proceeds by way of an SN2 mechanism; a water molecule initiates in-line nucleophilic attack. The dUTPase binding pocket is highly specific for uracil. Phosphate chain coordination involves Mg2+ and is analogous to that of DNA polymerases. Because of conformational changes in the enzyme during catalysis, most crystal structures have not resolved the residues in the C-terminus. However, recent high-resolution structures are beginning to provide in-depth structural information about this region of the protein.The dUTPase family of enzymes also shows promise as novel targets for anticancer and antimicrobial therapies. dUTPase is upregulated in human tumor cells. In addition, dUTPase inhibitors could also fight infectious diseases such as malaria and tuberculosis. In these respective pathogens, Plasmodium falciparum and Mycobacterium tuberculosis, the biosynthesis of dTMP relies exclusively on dUTPase activity.
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PMID:Keeping uracil out of DNA: physiological role, structure and catalytic mechanism of dUTPases. 1883 22

New treatments need to be developed for the significant human diseases of toxoplasmosis and malaria to circumvent problems with current treatments and drug resistance. Apicomplexan parasites causing these lethal diseases are deficient in pyrimidine salvage, suggesting that selective inhibition of de novo pyrimidine biosynthesis can lead to a severe loss of uridine 5'-monophosphate (UMP) and thymidine 5'-monophosphate (dTMP) pools, thereby inhibiting parasite RNA and DNA synthesis. Disruption of Toxoplasma gondii carbamoyl phosphate synthetase II (CPSII) induces a severe uracil auxotrophy with no detectable parasite replication in vitro and complete attenuation of virulence in mice. Here we show that a CPSII cDNA minigene efficiently complements the uracil auxotrophy of CPSII-deficient mutants, restoring parasite growth and virulence. Our complementation assays reveal that engineered mutations within, or proximal to, the catalytic triad of the N-terminal glutamine amidotransferase (GATase) domain inactivate the complementation activity of T. gondii CPSII and demonstrate a critical dependence on the apicomplexan CPSII GATase domain in vivo. Surprisingly, indels present within the T. gondii CPSII GATase domain as well as the C-terminal allosteric regulatory domain are found to be essential. In addition, several mutations directed at residues implicated in allosteric regulation in Escherichia coli CPS either abolish or markedly suppress complementation and further define the functional importance of the allosteric regulatory region. Collectively, these findings identify novel features of T. gondii CPSII as potential parasite-selective targets for drug development.
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PMID:Genetic identification of essential indels and domains in carbamoyl phosphate synthetase II of Toxoplasma gondii. 1899 49

Genome sequences of Plasmodium falciparum allow for global analysis of drug responses to antimalarial agents. It was of interest to learn how DNA microarrays may be used to study drug action in malaria parasites. In one large, tightly controlled study involving 123 microarray hybridizations between cDNA from isogenic drug-sensitive and drug-resistant parasites, a lethal antifolate (WR99210) failed to over-produce RNA for the genetically proven principal target, dihydrofolate reductase-thymidylate synthase (DHFR-TS). This transcriptional rigidity carried over to metabolically related RNA encoding folate and pyrimidine biosynthesis, as well as to the rest of the parasite genome. No genes were reproducibly up-regulated by more than 2-fold until 24 h after initial drug exposure, even though clonal viability decreased by 50% within 6 h. We predicted and showed that while the parasites do not mount protective transcriptional responses to antifolates in real time, P. falciparum cells transfected with human DHFR gene, and adapted to long-term WR99210 exposure, adjusted the hard-wired transcriptome itself to thrive in the presence of the drug. A system-wide incapacity for changing RNA levels in response to specific metabolic perturbations may contribute to selective vulnerabilities of Plasmodium falciparum to lethal antimetabolites. In addition, such regulation affects how DNA microarrays are used to understand the mode of action of antimetabolites.
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PMID:A genetically hard-wired metabolic transcriptome in Plasmodium falciparum fails to mount protective responses to lethal antifolates. 1902 12

The development of antimalarial drugs involving novel mechanisms of action is of imminent importance. Several potential drug candidates of synthetic and natural origin as well as their combination therapies are currently being evaluated for their efficacy against drug-resistant strains of the parasite. Various plasmodial targets/pathways, such as the Purine salvage pathway, Pyrimidine biosynthesis pathway and also the processes in the apicoplast, have been identified and are being utilized for the discovery and development of novel antimalarial therapies. This article provides an overview of the latest developments in terms of cell and molecular biology that will improve the knowledge related to drug-resistant malaria and to new molecular targets.
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PMID:Molecular and biological aspects of antimalarial resistance in Plasmodium falciparum and Plasmodium vivax. 1927 64

Pyrimidine biosynthesis is an attractive drug target in a variety of organisms, including humans and the malaria parasite Plasmodium falciparum. Dihydroorotate dehydrogenase, an enzyme catalyzing the only redox reaction of the pyrimidine biosynthesis pathway, is a well-characterized target for chemotherapeutical intervention. In this study, we have applied SPROUT-LeadOpt, a software package for structure-based drug discovery and lead optimization, to improve the binding of the active metabolite of the anti-inflammatory drug leflunomide to the target cavities of the P. falciparum and human dihydroorotate dehydrogenases. Following synthesis of a library of compounds based upon the SPROUT-optimized molecular scaffolds, a series of inhibitors generally showing good inhibitory activity was obtained, in keeping with the SPROUT-LeadOpt predictions. Furthermore, cocrystal structures of five of these SPROUT-designed inhibitors bound in the ubiquinone binding cavity of the human dihydroorotate dehydrogenase are also analyzed.
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PMID:Structure-based design, synthesis, and characterization of inhibitors of human and Plasmodium falciparum dihydroorotate dehydrogenases. 1935 Nov 52

Mitochondria in malaria parasites have some unusual evolutionary and functional features. The drastic reduction in the size of their mitochondrial genome, encoding just three proteins, appears to have originated at the point of divergence of dinoflagellates and apicomplexan parasites from ciliates and may have accompanied the acquisition of plastids by the former. Unusual translational machinery as revealed by the highly fragmented mitochondrial ribosomal RNA genes also appears to have originated at this deflection point. Some of the biochemical properties of malarial mitochondria also appear to be unconventional. Although tricarboxylic acid cycle enzymes are encoded by the genome, they do not appear to be involved in the full oxidation of glucose to fuel mitochondrial ATP synthesis in the blood stages of malaria parasites. A critical role of the mitochondrial electron transport chain appears to be to serve pyrimidine biosynthesis. In spite of their minimal nature, Plasmodium mitochondria are attractive targets for antimalarial drugs.
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PMID:Mitochondrial evolution and functions in malaria parasites. 1957 61

Malaria is a major worldwide public health threat with worrying social and economic burdens due to the rapid emergence of multidrug-resistant Plasmodium falciparum strains. As a result, there is an urgent need to find novel drugs that might overcome clinical resistance to marketed antimalarials. In recent years, the mitochondrial electron transport chain (mtETC) has been explored for the development of new antimalarials. Type II NADH:quinone oxidoreductase (PfNDH2), succinate dehydrogenase (SDH) and cytochrome bc1 have become a major focus of those efforts, leading to several studies of its biochemistry and the design of potent inhibitors. Furthermore, de novo pyrimidine biosynthesis in malaria parasites, particularly dihydroorotate dehydrogenase (PfDHODH), is also receiving increasing attention. The enzymes involved in the mtETC are valuable targets in malaria chemotherapy, not only because they play a critical role in metabolic pathways of P. falciparum, but also because they differ significantly from the analogous mammalian system. Inhibition of such enzymes results in the shutdown of mitochondrial electron flow, leading to the arrest of pyrimidine biosynthesis and consequent parasite death. In this review, we aim to outline recent advances in the inhibition of mitochondrial metabolic pathways, highlighting the major classes of known inhibitors and those that are currently being developed.
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PMID:Inhibitors of the mitochondrial electron transport chain and de novo pyrimidine biosynthesis as antimalarials: The present status. 2015 68

Malaria remains a globally prevalent infectious disease that leads to significant morbidity and mortality. While there are a number of drugs approved for its treatment, drug resistance has compromised most of them, making the development of new drugs for the treatment and prevention of malaria essential. The completion of the Plasmodium falciparum genome and a growing understanding of parasite biology are fueling the search for novel drug targets. Despite this, few targets have been chemically validated in vivo. The pyrimidine biosynthetic pathway illustrates one of the best examples of successful identification of anti-malarial drug targets. This review focuses on recent studies to exploit the fourth enzyme in the de novo pyrimidine biosynthetic pathway of P. falciparum, dihydroorotate dehydrogenase (PfDHODH), as a new target for drug discovery. Several chemical scaffolds have been identified by high throughput screening as potent inhibitors of PfDHODH and these show strong selectivity for the malarial enzyme over that from the human host. Potent activity against parasites in whole cell models with good correlation between activity on the enzyme and the parasite have also been observed for a number of the identified series. Lead optimization of a triazolopyrimidine-based series has identified an analog with prolonged plasma exposure, that is orally bioavailable, and which shows good efficacy against the in vivo mouse model of the disease. These data provide strong evidence that PfDHODH is a validated target for the identification of new antimalarial chemotherapy. The challenge remains to identify compounds with the necessary combination of potency and metabolic stability to allow identification of a clinical candidate.
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PMID:Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy. 2033 17


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