Isoprenoid biosynthesis in the erythrocytic stages of Plasmodium falciparum

Jordão, Fabiana Morandi; Kimura, Emı́lia A.; Katzin, Alejandro M.

doi:10.1590/s0074-02762011000900018

Cited by 35 publications

(41 citation statements)

References 80 publications

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“…The NMVA (MEP) pathway is absent in humans and essential to Plasmodium survival. It is thus a potential source of targets for the development of novel antimalarials (16). The apicoplast and digestive vacuole are distinct cellular compartments (organelles).…”

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confidence: 99%

In Vivo Antimalarial Activity and Mechanisms of Action of 4-Nerolidylcatechol Derivatives

Silva

Nogueira

Pinto

et al. 2015

Antimicrob Agents Chemother

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confidence: 99%

In Vivo Antimalarial Activity and Mechanisms of Action of 4-Nerolidylcatechol Derivatives

Silva

Nogueira

Pinto

et al. 2015

Antimicrob Agents Chemother

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“…We evaluated the combination of four drugs, three of them (fosmidomycin, nerolidol and risedronate) inhibiting parasite growth at some point in the MEP/isoprenoid pathway in intraerythrocytic stages of P. falciparum (6,7,8). We also evaluated the effect of squalestatin on P. falciparum growth.…”

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confidence: 99%

“…We have previously demonstrated that the isoprenoid biosynthesis pathway is functionally active in the intraerythrocytic stages of Plasmodium falciparum and that final products of this pathway such as dolichol of 11 to 12 isoprenic units (4), ubiquinones (5), isoprenylated/dolichylated proteins, carotenoids, menaquinone, and tocopherol are biosynthesized by this parasite (6). Several inhibitors of enzymes of the methyl erythritol diphosphate (MEP) and isoprenoid pathways were described as potential antimalarial drugs (6).…”

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confidence: 99%

“…Several inhibitors of enzymes of the methyl erythritol diphosphate (MEP) and isoprenoid pathways were described as potential antimalarial drugs (6).…”

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“…Additionally, our group has shown that nerolidol inhibited the synthesis of several final products of the isoprenoid biosynthesis, such as coenzyme Q and dolichol, and also protein isoprenylation (6,21). As risedronate is also an inhibitor of protein isoprenylation (8), the subadditive effect detected when risedronate is combined with nerolidol may indicate that the two compounds act at the same target of isoprenoid pathways.…”

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In Vitro Antimalarial Activity of Different Inhibitors of the Plasmodial Isoprenoid Synthesis Pathway

Silva

Saito

Peres

et al. 2015

Antimicrob Agents Chemother

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Previous studies have shown that fosmidomycin, risedronate, and nerolidol exert antimalarial activity in vitro. We included squalestatin, an inhibitor of the isoprenoid metabolism in Erwinia uredovora, and found that combinations of compounds which act on different targets of the plasmodial isoprenoid pathway possess important supra-additivity effects.M alaria expansion in some areas has been attributed to the failure of vector-control policies and, mainly, to the increase of parasite resistance to drugs commonly used for its therapy (1). This alarming scenario has fuelled research in new antimalarial drugs, and, with the sequencing of parasite genomes, new potential drug targets have emerged. Burrows et al. published a review discussing the strategies for designing the next generation of medicines for malaria control (2). A metabolic pathway that may be a likely target for evaluating potential antimalarials is the isoprenoid pathway. The first intermediates are biosynthesized in the apicoplast, which is an organelle present in protozoan parasites of the subphylum Apicomplexa, including Plasmodia (3).We have previously demonstrated that the isoprenoid biosynthesis pathway is functionally active in the intraerythrocytic stages of Plasmodium falciparum and that final products of this pathway such as dolichol of 11 to 12 isoprenic units (4), ubiquinones (5), isoprenylated/dolichylated proteins, carotenoids, menaquinone, and tocopherol are biosynthesized by this parasite (6). Several inhibitors of enzymes of the methyl erythritol diphosphate (MEP) and isoprenoid pathways were described as potential antimalarial drugs (6).Our aim in this work was to identify and validate different targets in the isoprenoid pathway in P. falciparum intraerythrocytic stages. We evaluated the combination of four drugs, three of them (fosmidomycin, nerolidol and risedronate) inhibiting parasite growth at some point in the MEP/isoprenoid pathway in intraerythrocytic stages of P. falciparum (6,7,8). We also evaluated the effect of squalestatin on P. falciparum growth. This drug is an inhibitor of the phytoene synthase in Erwinia uredovora (9, 10). Importantly, an enzyme with phytoene synthase activity was described in intraerythrocytic stages of P. falciparum (11).Parasites of P. falciparum clone 3D7 were cultured according to the protocol described by Trager and Jensen (12) where human serum was replaced by Albumax I (0.5%) (4). Stocks (1 mM) of squalestatin, risedronate, and fosmidomycin were prepared in RPMI medium, whereas nerolidol was diluted in ethanol, and all drugs were stored at Ϫ70°C.Assays were performed in 96-well microtiter plates containing 100 l of 3D7 culture at 1% parasitemia and 3% hematocrit and 100 l of the appropriate drug or drug combination in RPMI medium. Parasite growth was determined using Giemsa-stained smears immediately before the start of the assay and at intervals of 24 to 48 h. Vehicle controls were included on each plate. All tests were performed in triplicate for three independent experiments.Values for 5...

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The biochemistry ofPlasmodium falciparum

Ginsburg

2016

Advances in Malaria Research

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Isoprenoid biosynthesis in the erythrocytic stages of Plasmodium falciparum

Cited by 35 publications

References 80 publications

In Vivo Antimalarial Activity and Mechanisms of Action of 4-Nerolidylcatechol Derivatives

In Vivo Antimalarial Activity and Mechanisms of Action of 4-Nerolidylcatechol Derivatives

In Vitro Antimalarial Activity of Different Inhibitors of the Plasmodial Isoprenoid Synthesis Pathway

The biochemistry ofPlasmodium falciparum

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