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.