Validation of the hexose transporter of
            <i>Plasmodium falciparum</i>
            as  a novel drug target

Joët, Thierry; Eckstein-Ludwig, Ursula; Morin, Christophe; Krishna, Sanjeev

doi:10.1073/pnas.1330865100

Cited by 132 publications

(166 citation statements)

References 16 publications

(17 reference statements)

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“…A study using O-3 hexose derivatives demonstrated a potent and selective inhibition of PfHT. Moreover, the glucosederived inhibitors show an inhibition of asexual blood stage P. falciparum growth in vitro and of different P. berghei life cycle stages in vivo, thereby validating PfHT as a valuable antimalarial drug target (46). This assumption was further supported by a study showing that PfHT is essential for both P. falciparum and P. berghei (47).…”

Section: P Falciparum Glucose Transportersmentioning

confidence: 73%

Glucose‐6‐phosphate metabolism in Plasmodium falciparum

2012

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Malaria is still one of the most threatening diseases worldwide. The high drug resistance rates of malarial parasites make its eradication difficult and furthermore necessitate the development of new antimalarial drugs. Plasmodium falciparum is responsible for severe malaria and therefore of special interest with regard to drug development. Plasmodium parasites are highly dependent on glucose and very sensitive to oxidative stress; two observations that drew interest to the pentose phosphate pathway (PPP) with its key enzyme glucose‐6‐phosphate dehydrogenase (G6PD). A central position of the PPP for malaria parasites is supported by the fact that human G6PD deficiency protects to a certain degree from malaria infections. Plasmodium parasites and the human host possess a complete PPP, both of which seem to be important for the parasites. Interestingly, there are major differences between parasite and human G6PD, making the enzyme of Plasmodium a promising target for antimalarial drug design. This review gives an overview of the current state of research on glucose‐6‐phosphate metabolism in P. falciparum and its impact on malaria infections. Moreover, the unique characteristics of the enzyme G6PD in P. falciparum are discussed, upon which its current status as promising target for drug development is based. © 2012 IUBMB IUBMB Life, 64(7): 603–611, 2012

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Section: P Falciparum Glucose Transportersmentioning

confidence: 73%

Glucose‐6‐phosphate metabolism in Plasmodium falciparum

2012

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“…The increase in levels of N-carbamoyl-L-aspartate and dihydroorotate in atovaquone-treated cultures reflects the indirect inhibition of dihydroorotate dehydrogenase activity following primary inhibition of ubiquinol oxidation by the cytochrome bc 1 complex (22). Interestingly, primaquine and the metabolic inhibitors, buthionine sulfoximine, 2-deoxyglucose, compound 3361 (45), and sodium fluoroacetate did not elicit reproducible metabolic fingerprints under these conditions ( Fig. 2A).…”

Section: Resultsmentioning

confidence: 94%

Metabolomics-Based Screening of the Malaria Box Reveals both Novel and Established Mechanisms of Action

Creek

Chua

Cobbold

et al. 2016

Antimicrob Agents Chemother

130

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e High-throughput phenotypic screening of chemical libraries has resulted in the identification of thousands of compounds with potent antimalarial activity, although in most cases, the mechanism(s) of action of these compounds remains unknown. Here we have investigated the mode of action of 90 antimalarial compounds derived from the Malaria Box collection using high-coverage, untargeted metabolomics analysis. Approximately half of the tested compounds induced significant metabolic perturbations in in vitro cultures of Plasmodium falciparum. In most cases, the metabolic profiles were highly correlated with known antimalarials, in particular artemisinin, the 4-aminoquinolines, or atovaquone. Select Malaria Box compounds also induced changes in intermediates in essential metabolic pathways, such as isoprenoid biosynthesis (i.e., 2-C-methyl-D-erythritol 2,4-cyclodiphosphate) and linolenic acid metabolism (i.e., traumatic acid). This study provides a comprehensive database of the metabolic perturbations induced by chemically diverse inhibitors and highlights the utility of metabolomics for triaging new lead compounds and defining specific modes of action, which will assist with the development and optimization of new antimalarial drugs. Malaria remains a major global health problem, and there is a pressing need to discover and develop new antimalarials. Traditional antimalarial drugs have been severely undermined by the emergence of drug-resistant strains and current treatments rely heavily on artemisinin-based combination therapies. Alarmingly, artemisinin resistance has arisen in Southeast Asia during the last decade, highlighting the urgent need for new antimalarials (1). Extensive efforts to produce a malaria vaccine have met limited success and a pipeline of new antimalarial drugs will be required to mitigate extensive morbidity and mortality from malaria for the foreseeable future (2).High-throughput phenotypic screening of chemical libraries against the malaria parasite, Plasmodium falciparum, has provided a major step forward in the discovery of novel antimalarial compounds. Almost 30,000 compounds that selectively inhibit growth of cultured P. falciparum asexual red blood cell (RBC) stages have been identified in these screens, providing excellent starting points for the discovery of new antimalarial drugs (3-5). A prioritized collection of these "hit" compounds, known as the Malaria Box, has been assembled by the Medicines for Malaria Venture (MMV) and provided free to the research community to facilitate this drug development pipeline (6).A key limitation to the further optimization of many of these compounds is the lack of information on their mode of action. While not essential for registration, information on the mode of action of inhibitors discovered in phenotypic screens will significantly accelerate drug development by allowing structure-based drug design, monitoring of activity, toxicity and resistance, and facilitation of rational clinical usage in combination with other medicines. Furthermore, in...

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“…3A). Similarly, other genes needed for the acquisition of nutrients in the malarial parasite such as PfHT and PfNT1 (malaria hexose transporter and nucleoside transporter) have been shown to be up-regulated during the trophozoite/ schizont stages (7,8).…”

Section: Discussionmentioning

confidence: 99%

Aquaglyceroporin PbAQP during intraerythrocytic development of the malaria parasite Plasmodium berghei

Promeneur

Liu

Maciel

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The malaria parasite can use host plasma glycerol for lipid biosynthesis and membrane biogenesis during the asexual intraerythrocytic development. The molecular basis for glycerol uptake into the parasite is undefined. We hypothesize that the Plasmodium aquaglyceroporin provides the pathway for glycerol uptake into the malaria parasite. To test this hypothesis, we identified the orthologue of Plasmodium falciparum aquaglyceroporin (PfAQP) in the rodent malaria parasite, Plasmodium berghei (PbAQP), and examined the biological role of PbAQP by performing a targeted deletion of the PbAQP gene. PbAQP and PfAQP are 62% identical in sequence. In contrast to the canonical NPA (Asn-Pro-Ala) motifs in most aquaporins, the PbAQP has NLA (Asn-Leu-Ala) and NPS (Asn-Leu-Ser) in those positions. PbAQP expressed in Xenopus oocytes was permeable to water and glycerol, suggesting that PbAQP is an aquaglyceroporin. In P. berghei, PbAQP was localized to the parasite plasma membrane. The PbAQP-null parasites were viable; however, they were highly deficient in glycerol transport. In addition, they proliferated more slowly compared with the WT parasites, and mice infected with PbAQP-null parasites survived longer. Taken together, these findings suggest that PbAQP provides the pathway for the entry of glycerol into P. berghei and contributes to the growth of the parasite during the asexual intraerythrocytic stages of infection. In conclusion, we demonstrate here that PbAQP plays an important role in the blood-stage development of the rodent malaria parasite during infection in mice and could be added to the list of targets for the design of antimalarial drugs.falciparum ͉ knockout ͉ glycerol

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Validation of the hexose transporter of Plasmodium falciparum as a novel drug target

Cited by 132 publications

References 16 publications

Glucose‐6‐phosphate metabolism in Plasmodium falciparum

Glucose‐6‐phosphate metabolism in Plasmodium falciparum

Metabolomics-Based Screening of the Malaria Box Reveals both Novel and Established Mechanisms of Action

Aquaglyceroporin PbAQP during intraerythrocytic development of the malaria parasite Plasmodium berghei

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