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)

A simple, efficient, sensitive, reproducible and high throughput assay for measuring the cytoadhesion of Plasmodium falciparum-infected red blood cells (human malaria) is described. The assay format uses 96-well microplates, with the number of P. falciparum parasitized erythrocytes bound determined by measuring Plasmodium specific lactic dehydrogenase activity colorimetrically (absorbance at 655 nm) using the 3-acetylpyridine analog of nicotinamide adenine dinucleotide, nitro blue tetrazolium and diaphorase. The results of the described microplate assay were found to be comparable to those using microscopic analysis but much less time consuming.
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PMID:A high capacity in vitro assay for measuring the cytoadherence of Plasmodium falciparum-infected erythrocytes. 1055 1

A role for the flavoprotein NRH:quinone oxidoreductase 2 (NQO2, QR2) in human diseases such as malaria, leukemia and neurodegeneration has been proposed. In order to explore the potential of NQO2 as a therapeutic target, we have developed potent and selective mechanism-based inhibitors centered on the indolequinone pharmacophore. The compounds show remarkable selectivity for NQO2 over the closely related flavoprotein NQO1, with small structural changes defining selectivity. Biochemical studies confirmed the mechanism-based inhibition, whereas X-ray crystallography and mass spectrometry revealed the nature of the inhibitor interaction with the protein. These indolequinones represent the first mechanism-based inhibitors of NQO2, and their novel mode of action involving alkylation of the flavin cofactor, provides significant advantages over existing competitive inhibitors in terms of potency and irreversibility, and will open new opportunities to define the role of NQO2 in disease.
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PMID:Mechanism-based inhibition of quinone reductase 2 (NQO2): selectivity for NQO2 over NQO1 and structural basis for flavoprotein inhibition. 2150 32

Primaquine is a traditional antimalarial drug with low parasitic resistance and generally good acceptance at higher doses, which has been used for over 60 years in malaria treatment. However, several limitations related to its hematotoxicity have been reported. It is believed that this toxicity comes from the hydroxylation of the C-5 and C-6 positions of its 8-aminoquinoline ring before binding to the molecular target: the quinone reductase II (NQO2) human protein. In this study we propose primaquine derivatives, with substitution at position C-6 of the 8-aminoquinoline ring, planned to have better binding to NQO2, compared to primaquine, but with a reduced toxicity related to the C-5 position being possible to be oxidized. On this sense the proposed analogues were suggested in order to reduce or inhibit hydroxylation and further oxidation to hemotoxic metabolites. Five C-6 substituted primaquine analogues were selected by de novo design and further submitted to docking and molecular dynamics simulations. Our results suggest that all analogues bind better to NQO2 than primaquine and may become better antimalarials. However, the analogues 3 and 4 are predicted to have a better activity/toxicity balance.
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PMID:Structure-based de novo design, molecular docking and molecular dynamics of primaquine analogues acting as quinone reductase II inhibitors. 2652 Dec 7

Antimalarial combination therapies play a crucial role in preventing the emergence of drug-resistant Plasmodium parasites. Although artemisinin-based combination therapies (ACTs) comprise the majority of these formulations, inhibitors of the mitochondrial cytochrome bc1 complex (cyt bc1) are among the few compounds that are effective for both acute antimalarial treatment and prophylaxis. There are two known sites for inhibition within cyt bc1: atovaquone (ATV) blocks the quinol oxidase (Qo) site of cyt bc1, while some members of the endochin-like quinolone (ELQ) family, including preclinical candidate ELQ-300, inhibit the quinone reductase (Qi) site and retain full potency against ATV-resistant Plasmodium falciparum strains with Qo site mutations. Here, we provide the first in vivo comparison of ATV, ELQ-300, and combination therapy consisting of ATV plus ELQ-300 (ATV:ELQ-300), using P. yoelii murine models of malaria. In our monotherapy assessments, we found that ATV functioned as a single-dose curative compound in suppressive tests whereas ELQ-300 demonstrated a unique cumulative dosing effect that successfully blocked recrudescence even in a high-parasitemia acute infection model. ATV:ELQ-300 therapy was highly synergistic, and the combination was curative with a single combined dose of 1 mg/kg of body weight. Compared to the ATV:proguanil (Malarone) formulation, ATV:ELQ-300 was more efficacious in multiday, acute infection models and was equally effective at blocking the emergence of ATV-resistant parasites. Ultimately, our data suggest that dual-site inhibition of cyt bc1 is a valuable strategy for antimalarial combination therapy and that Qi site inhibitors such as ELQ-300 represent valuable partner drugs for the clinically successful Qo site inhibitor ATV.
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PMID:Atovaquone and ELQ-300 Combination Therapy as a Novel Dual-Site Cytochrome bc1 Inhibition Strategy for Malaria. 2727 Feb 85

Chorismate synthase (Cs) is the last enzyme of the main trunk of shikimate pathway and catalyzes formation of chorismate, a major aromatic metabolite precursor. We have previously reported that Cs is highly conserved across different Plasmodium sp. Here we report that Cs from malaria parasites are bifunctional enzymes through expression and functional studies of two recombinant proteins rPfCs (Cs from P. falciparum) and rPvCs (Cs from P. vivax). We confirm bifunctional activity of both rPfCs and rPvCs based on their ability to catalyze formation of chorismate under aerobic conditions as well as their ability to catalyze generation of reduced flavin mononucleotide (FMN) as assessed through diaphorase assay.
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PMID:Chorismate synthase from malaria parasites is bifunctional enzyme. 3138 47