Why is the Plasmodium falciparum hexose transporter a promising new drug target?

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.