Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pyrimidine metabolism is a major route for therapeutic intervention against malaria. Here we report inhibition and structural studies on the deoxyuridine nucleotidohydrolase from the malaria parasite Plasmodium falciparum (PfdUTPase). We have identified a series of triphenylmethane derivatives of deoxyuridine with antimalarial activity in vitro which inhibit specifically the Plasmodium dUTPase versus the human enzyme. A 2.4 Angstrom crystal structure of PfdUTPase in complex with one of these inhibitors reveals an atypical trimeric enzyme in which the triphenylmethane derivative can be seen to select for PfdUTPase by way of interactions between the trityl group and the side chains of residues Phe46 and Ile117. Immunofluorescence microscopy studies of parasitized red blood cells reveal that enzyme concentrations are highest during the trophozoite/schizont stages, suggesting that PfdUTPase has a major role in DNA replication. Taken together the data show that PfdUTPase may be considered as an antimalarial drug target.
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PMID:dUTPase as a platform for antimalarial drug design: structural basis for the selectivity of a class of nucleoside inhibitors. 1569 76

Parasitic apicomplexans are responsible for some of the most severe worldwide health problems, including malaria, toxoplasmosis and cryptosporidiosis. These parasites are characterized by a bifunctional enzyme, dihydrofolate reductase-thymidylate synthase (DHFR-TS), which has a crucial role in pyrimidine biosynthesis. Inhibitors of DHFR have been successful in the treatment of toxoplasmosis and malaria. However, there is currently no effective therapy for cryptosporidiosis, and despite early successes against malaria, resistance to DHFR inhibitors in malaria parasites has now become a global problem. Novel DHFR inhibitors, designed using the recently revealed crystal structures of the enzymes from two parasitic protozoa, are in development.
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PMID:Targeting DHFR in parasitic protozoa. 1571 61

Markers of Plasmodium falciparum resistance to chloroquine (CQ) and pyrimethamine-sulfadoxine (PYR-SDX) are widespread in areas where malaria is endemic. In an area where the use PYR-SDX is negligible, the Ashanti Region of Ghana, West Africa, adult individuals were enrolled in an analysis of CQ- and PYR-SDX-associated molecular resistance markers in 2001 (n = 177) and 2003 (n = 180). Parasite prevalence, as assessed by PCR assays, were 56.5 and 48.8% in 2001 and 2003, respectively. A high frequency of CQ, PYR, and SDX resistance markers was observed, whereby, as a weak trend, the frequency was higher in 2003. The quintuple combination of three pfdhfr mutations and two pfdhps mutations has previously been recognized to be the most important determinant of PYR-SDX resistance. Approximately 60% of parasite carriers harbored fourfold mutated parasites, indicative of a considerable risk for a switch to high-level PYR-SDX resistance in an area where the rate of PYR-SDX use is low. Among the factors contributing to the high frequency of PYR-SDX resistance-associated mutations are background use of PYR-SDX, past use of PYR for malaria prophylaxis, cross-resistance of trimethoprim with PYR, and the sufficient biological fitness of resistant parasites in the absence of drug pressure.
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PMID:High prevalence of markers for sulfadoxine and pyrimethamine resistance in Plasmodium falciparum in the absence of drug pressure in the Ashanti region of Ghana. 1572 9

Antimalarial drug resistance in endemic malaria zones is first detected in vitro; when it reaches a certain threshold, it becomes perceptible and is expressed in therapeutic failure among subjects only slightly or not at all immune. This work conducted in northern Abidjan (Cote d'Ivoire) studied children with uncomplicated malaria, who were followed for 14 days (during the year 2000) in accordance with the WHO protocol for surveillance of antimalarial drug resistance. Concomitantly, the Plasmodium falciparum isolates were cultured in the presence of variable concentrations of chloroquine, pyrimethamine and quinine during in vitro chemosensitivity tests. The RPMI 1640 used as medium for the pyrimethamine did not contain PABA (para-amino benzoic acid) or folic acid. In all, 114 in vitro tests were completed, 33 to chloroquine, 32 to pyrimethamine, and 49 to quinine. Therapeutic efficacy was tested in 65 patients: 33 to chloroquine and 32 to sulfadoxine-pyrimethamine (SP). The results found 36% of the isolates were chloroquine-resistant (CQ-R) and 33% of the patients treated with chloroquine did not respond adequately (therapeutic failure, TF). The 12 CQ-R isolates corresponded to 11 TF subjects and 1 patient with adequate clinical and parasitological response. The concordance between the two tests was good (kappa=0.93). For pyrimethamine, 37.5% of the isolates were resistant (PYR-R), and 37.5% of patients responded adequately to SP. The 12 PYR-R isolates were from 12 TF subjects, so that kappa=1.0, when pyrimethamine resistance is defined as IC50 > 2,000 nM. Because of the elevated rate of chloroquine resistance, the national antimalaria program has recommended since July 2003 that amodiaquine be used as a first-line drug, to replace chloroquine. The relatively elevated number of TF with SP are a source of concern, because it is used in Yopougon (Abidjan). Additional studies to assess the prevalence of resistance to this combination in other areas of Abidjan city (Cote d' Ivoire) would be useful.
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PMID:[Limits of the efficacy of chloroquine and sulfadoxine-pyrimethamine in Northern Abidjan (Cote d'Ivoire): Combined in vivo and in vitro studies]. 1574 69

Like all parasitic protozoa, the human malaria parasite Plasmodium falciparum lacks the enzymes required for de novo synthesis of purines and it is therefore reliant upon the salvage of these compounds from the external environment. P. falciparum equilibrative nucleoside transporter 1 (PfENT1) is a nucleoside transporter that has been localized to the plasma membrane of the intraerythrocytic form of the parasite. In this study we have characterized the transport of purine and pyrimidine nucleosides across the plasma membrane of 'isolated' trophozoite-stage P. falciparum parasites and compared the transport characteristics of the parasite with those of PfENT1 expressed in Xenopus oocytes. The transport of nucleosides into the parasite: (i) was, in the case of adenosine, inosine and thymidine, very fast, equilibrating within a few seconds; (ii) was of low affinity [K(m) (adenosine) = 1.45 +/- 0.25 mM; K(m) (thymidine) = 1.11 +/- 0.09 mM]; and (iii) showed 'cross-competition' for adenosine, inosine and thymidine, but not cytidine. The kinetic characteristics of nucleoside transport in intact parasites matched very closely those of PfENT1 expressed in Xenopus oocytes [K(m) (adenosine) = 1.86 +/- 0.28 mM; K(m) (thymidine) = 1.33 +/- 0.17 mM]. Furthermore, PfENT1 transported adenosine, inosine and thymidine, with a cross-competition profile the same as that seen for isolated parasites. The data are consistent with PfENT1 serving as a major route for the uptake of nucleosides across the parasite plasma membrane.
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PMID:Transport of nucleosides across the Plasmodium falciparum parasite plasma membrane has characteristics of PfENT1. 1662 74

With >1 million deaths annually, mostly among children in sub-Saharan Africa, malaria poses one of the most critical challenges in medicine today. Although introduction of the artemisinin class of antimalarial drugs has offered a temporary solution to the problem of drug resistance, new antimalarial drugs are needed to ensure effective control of the disease in the future. Herein, we have investigated members of the methionine aminopeptidase family as potential antimalarial targets. The Plasmodium falciparum methionine aminopeptidase 1b (PfMetAP1b), one of four MetAP proteins encoded in the P. falciparum genome, was cloned, overexpressed, purified, and used to screen a 175,000-compound library for inhibitors. A family of structurally related inhibitors containing a 2-(2-pyridinyl)-pyrimidine core was identified. Structure/activity studies led to the identification of a potent PfMetAP1b inhibitor, XC11, with an IC(50) of 112 nM. XC11 was highly selective for PfMetAP1b and did not exhibit significant cytotoxicity against primary human fibroblasts. Most importantly, XC11 inhibited the proliferation of P. falciparum strains 3D7 [chloroquine (CQ)-sensitive] and Dd2 (multidrug-resistant) in vitro and is active in mouse malaria models for both CQ-sensitive and CQ-resistant strains. These results suggest that PfMetAP1b is a promising target and XC11 is an important lead compound for the development of novel antimalarial drugs.
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PMID:Inhibitors of Plasmodium falciparum methionine aminopeptidase 1b possess antimalarial activity. 1698 82

Pyrimidine biosynthesis presents an attractive drug target in malaria parasites due to the absence of a pyrimidine salvage pathway. A set of compounds designed to inhibit the Plasmodium falciparum pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (PfDHODH) was synthesized. PfDHODH-specific inhibitors with low nanomolar binding affinities were identified that bind in the N-terminal hydrophobic channel of dihydroorotate dehydrogenase, the presumed site of ubiquinone binding during oxidation of dihydroorotate to orotate. These compounds also prevented growth of cultured parasites at low micromolar concentrations. Models that suggest the mode of inhibitor binding is based on shape complementarity, matching hydrophobic regions of inhibitor and enzyme, and interaction of inhibitors with amino acid residues F188, H185, and R265 are supported by mutagenesis data. These results further highlight PfDHODH as a promising new target for chemotherapeutic intervention in prevention of malaria and provide better understanding of the factors that determine specificity over human dihydroorotate dehydrogenase.
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PMID:Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase. 1722 60

The origin of all mitochondria can be traced to the symbiotic arrangement that resulted in the emergence of eukaryotes in a world that was exclusively populated by prokaryotes. This arrangement, however, has been in continuous genetic flux: the varying degrees of gene loss and transfer from the mitochondrial genome in different eukaryotic lineages seem to signify an ongoing 'conflict' between the host and the symbiont. Eukaryotic parasites belonging to the phylum Apicomplexa provide an excellent example to support this view. These organisms contain the smallest mitochondrial genomes known, with an organization that differs among various genera; one genus, Cryptosporidium, seems to have lost the entire mitochondrial genome. Here we show that erythrocytic stages of the human malaria parasite Plasmodium falciparum seem to maintain an active mitochondrial electron transport chain to serve just one metabolic function: regeneration of ubiquinone required as the electron acceptor for dihydroorotate dehydrogenase, an essential enzyme for pyrimidine biosynthesis. Transgenic P. falciparum parasites expressing Saccharomyces cerevisiae dihydroorotate dehydrogenase, which does not require ubiquinone as an electron acceptor, were completely resistant to inhibitors of mitochondrial electron transport. Maintenance of mitochondrial membrane potential, however, was essential in these parasites, as indicated by their hypersensitivity to proguanil, a drug that collapsed the membrane potential in the presence of electron transport inhibitors. Thus, acquisition of just one enzyme can render mitochondrial electron transport nonessential in erythrocytic stages of P. falciparum.
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PMID:Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum. 1733 44

Nested PCR and restriction analysis were used to detect mutations at codon 76 of Plasmodium falciparum chloroquine resistance transporter gene (pfcrt) and codon 59 of dihydrofolate reductase gene (dhfr) that indicate chloroquine (CQ) and pyrimethamine-sulfadoxine (PYR-SDX) resistance respectively. P. falciparum isolates from malaria-endemic area of Jazan showed CQ resistance rate (89.5%), the highest percentage of chloroquine resistance ever recorded in Saudi Arabia. One the other hand, 10.5% of isolates showed a PYR-SDX resistant allele as a first reported in the kingdom. The use of molecular markers as additional tools to map areas of chloroquine resistance was expected to contribute in the development of new strategies for therapeutic intervention towards malaria in Saudi Arabia.
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PMID:Detection of drug resistance markers for chloroquine and pyrimethamine-sulfadoxine in Jazan area, Saudi Arabia using PCR and restriction digestion. 1758 May 65

Plasmodium falciparum, the causative agent of human malaria, is totally dependent on de novo pyrimidine biosynthetic pathway. A gene encoding P. falciparum dihydroorotase (pfDHOase) was cloned and expressed in Escherichia coli as monofunctional enzyme. PfDHOase revealed a molecular mass of 42kDa. In gel filtration chromatography, the major enzyme activity eluted at 40kDa, indicating that it functions in a monomeric form. This was similarly observed using the native enzyme purified from P. falciparum. Interestingly, kinetic parameters of the enzyme and inhibitory effect by orotate and its 5-substituted derivatives parallel that found in mammalian type I DHOase. Thus, the malarial enzyme shares characteristics of both type I and type II DHOases. This study provides the monofunctional property of the parasite DHOase lending further insights into its differences from the human enzyme which forms part of a multifunctional protein.
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PMID:Dihydroorotase of human malarial parasite Plasmodium falciparum differs from host enzyme. 1808 26


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