The hexose transporter of Plasmodium falciparum is a worthy drug target

Despite substantial efforts at control over several decades, malaria is still a major global health problem as chemotherapy of malaria parasites is limited by established drug resistance and lack of novel treatment options. Intraerythrocytic stages of these parasites are wholly dependent upon host glucose for energy and malarial proteins involved in hexose permeation are therefore attractive new drug targets. For Plasmodium falciparum, the causative agent of severe malaria, a facilitative hexose transporter (PfHT), encoded by a single-copy gene mediates glucose uptake. We first established heterologous expression in Xenopus laevis to allow functional characterisation of PfHT. This review describes the value of using Xenopus oocytes in heterologous studies of P. falciparum-encoded proteins and summarises the properties of PfHT. Comparisons between Gluts (mammalian facilitative hexose transporters) and PfHT using this expression system have highlighted important mechanistic and structural differences between parasite and host proteins. Certain O-methyl derivatives of glucose proved particularly useful discriminators between mammalian transporters and PfHT. We exploited this selectivity and synthesised a long-chain O-3-hexose derivative (compound 3361) that potently inhibits PfHT expressed in oocytes and also kills P. falciparum when it is cultured in medium containing either glucose or fructose as a carbon source. To extend our observations to the second most important human malarial pathogen, we have cloned and expressed the Plasmodium vivax orthologue of PfHT, and demonstrate inhibition of glucose uptake by compound 3361. These findings validate malarial hexose transporters as a novel target. We now aim to design a new class of antimalarials by the discovery of highly specific inhibitors which could act with a broad spectrum of action on different Plasmodium spp. infections.