Exploiting the therapeutic potential of Plasmodium falciparum solute transporters

Staines, Henry M.; Derbyshire, Elvira T.; Slavic, Ksenija; Tattersall, Amanda; Vial, Henri; Krishna, Sanjeev

doi:10.1016/j.pt.2010.03.004

Cited by 30 publications

(37 citation statements)

References 125 publications

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“…Even if these could be predicted by orthology for about half of the candidates, experimental validations are still necessary to confirm or discover which they are. Extensive experimental work therefore needs to be done to further exploit such a rich source of potential targets (Staines et al, 2010). Some promising results nonetheless emerged in this field.…”

Section: Transportersmentioning

confidence: 99%

“…The P-type ATPases, PfATP4 and PfATP6, and the drug-resistance involved PfCRT and Pgh1 have also been expressed in such heterologous system, opening the road for functional studies (Martin et al, 2009). The number of known 3D-structures remains however extremely low, limited to PfAQP although a model has been proposed for PfHT1 based on the structure of E. coli permease (Staines et al, 2010).…”

Section: Transportersmentioning

confidence: 99%

“…Such experiments performed using rodent malaria models further indicated that some candidates, apparently dispensable for the asexual development, turned out important for the development of other parasite stages in insects or liver (Martin et al, 2009, Staines et al, 2004. Among all these candidates, PfHT1 is the only malarial transporter that has been validated both chemically and genetically (Staines et al, 2010). Gene deletion studies and D-glucose derivatives used as inhibitors confirmed the essential role of the hexose transporters for the asexual parasite development and other parasite stages (Blume et al, 2010, Slavic et al, 2011.…”

Section: Transportersmentioning

confidence: 99%

See 2 more Smart Citations

Advances in Antimalarial Drug Evaluation and New Targets for Antimalarials

Grellier¹,

Deregnaucourt²,

Isabelle³

2012

Malaria Parasites

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Section: Transportersmentioning

confidence: 99%

Section: Transportersmentioning

confidence: 99%

Section: Transportersmentioning

confidence: 99%

See 1 more Smart Citation

Advances in Antimalarial Drug Evaluation and New Targets for Antimalarials

Grellier¹,

Deregnaucourt²,

Isabelle³

2012

Malaria Parasites

View full text Add to dashboard Cite

“…Compound 3361 is also active against Plasmodium berghei liver and transmission stage parasites in infected mice (10), suggesting that PfHT is a promising target for full life cycle activity. However, while compound 3361 validates efforts to target PfHT, this compound is not itself considered drug-like and is therefore not a valid candidate for lead development (11). We have recently extended these earlier findings by identifying PfHT as a molecular target of the HIV protease inhibitor lopinavir, thus providing a link between lopinavir use and decreased malarial transmission in areas where HIV and malaria are both endemic (12).…”

mentioning

confidence: 95%

A Novel Fluorescence Resonance Energy Transfer-Based Screen in High-Throughput Format To Identify Inhibitors of Malarial and Human Glucose Transporters

Kraft

Heitmeier

Putanko

et al. 2016

Antimicrob Agents Chemother

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The glucose transporter PfHT is essential to the survival of the malaria parasite Plasmodium falciparum and has been shown to be a druggable target with high potential for pharmacological intervention. Identification of compounds against novel drug targets is crucial to combating resistance against current therapeutics. Here, we describe the development of a cell-based assay system readily adaptable to high-throughput screening that directly measures compound effects on PfHT-mediated glucose transport. Intracellular glucose concentrations are detected using a genetically encoded fluorescence resonance energy transfer (FRET)-based glucose sensor. This allows assessment of the ability of small molecules to inhibit glucose uptake with high accuracy (Z= factor of >0.8), thereby eliminating the need for radiolabeled substrates. Furthermore, we have adapted this assay to counterscreen PfHT hits against the human orthologues GLUT1, -2, -3, and -4. We report the identification of several hits after screening the Medicines for Malaria Venture (MMV) Malaria Box, a library of 400 compounds known to inhibit erythrocytic development of P. falciparum. Hit compounds were characterized by determining the half-maximal inhibitory concentration (IC 50 ) for the uptake of radiolabeled glucose into isolated P. falciparum parasites. One of our hits, compound MMV009085, shows high potency and orthologue selectivity, thereby successfully validating our assay for antimalarial screening. Malaria is a major threat to the human population in large areas of the world, affecting over 200 million people per year (1, 2). Beyond the effects of this disease on human life, malaria also cripples economic development and burdens the health care systems of countries where malaria is endemic (3). The emergence of parasites with resistance to even the most potent existing antimalarial drugs, such as the artemisinins (4), has made paramount the development of novel drugs that target essential pathways for parasite survival. Blood stage parasites utilize glucose for both biomass production and ATP synthesis (5). The malarial hexose transporter, Plasmodium falciparum hexose transporter (PfHT), first cloned by Woodrow et al. in 1999 (6), mediates parasite transport of glucose, fructose, mannose, and galactose (7). Since PfHT is essential for parasite survival (8), this protein is a highly promising molecular target for antimalarial drug development. This is supported by the ability of compound 3361, a glucose analogue that inhibits PfHT with high selectivity over the human orthologue GLUT1, to inhibit asexual intraerythrocytic growth in culture (9). Compound 3361 is also active against Plasmodium berghei liver and transmission stage parasites in infected mice (10), suggesting that PfHT is a promising target for full life cycle activity. However, while compound 3361 validates efforts to target PfHT, this compound is not itself considered drug-like and is therefore not a valid candidate for lead development (11). We have recently extended these earlier find...

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“…There is therefore an urgent need to discover new antimalarial drugs that act via novel drug targets. Robust validation of novel targets is critical to this process (30), and for technical and clinical reasons, this has been studied predominantly in the asexual erythrocytic stage of plasmodial parasites. Characterizing the nature of new targets during different stages of the parasite's life cycle can define their essentiality and therefore help in choosing those that are critical to the survival of most stages.…”

mentioning

confidence: 99%