title: Why is the Plasmodium falciparum hexose transporter a promising new drug target?
abstract: Chemotherapy of malaria parasites is limited by established drug resistance and lack of novel treatment options. Intraerythrocytic stages of Plasmodium falciparum, the causative agent of severe malaria, are wholly dependent upon host glucose for energy. A facilitative hexose transporter (PfHT), encoded by a single-copy gene, mediates glucose uptake and is therefore an attractive potential target. The authors first established heterologous expression in Xenopus laevis to allow functional characterisation of PfHT. They then used this expression system to compare the interaction of substrates with PfHT and mammalian Gluts (hexose transporters) and identified important differences between host and parasite transporters. Certain Omethyl derivatives of glucose proved to be particularly useful discriminators between mammalian transporters and PfHT. The authors exploited this selectivity and synthesised an O-3 hexose derivative that potently inhibits PfHT expressed in oocytes. This O-3 derivative (compound 3361) also kills cultured P. falciparum with comparable potency. Compound 3361 acts with reasonable specificity against PfHT orthologues encoded by other parasites such as Plasmodium vivax, Plasmodium yoelii and Plasmodium knowlesi. Multiplication of Plasmodium berghei in a mouse model is also significantly impeded by this compound. These findings validate PfHT as a novel target.
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004734:Energy Metabolism / Q000187:drug effects; D005285:Fermentation; D005632:Fructose / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008322:Mammals / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D010961:Plasmodium / Q000187:drug effects / Q000201:enzymology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014982:Xenopus laevis
chemical_list: D000962:Antimalarials; D009004:Monosaccharide Transport Proteins; D015800:Protozoan Proteins; D011993:Recombinant Fusion Proteins; C118145:hexose transporter 1 protein, Plasmodium falciparum; D005632:Fructose; D005947:Glucose