Structural Basis for Blocking Sugar Uptake into the Malaria Parasite Plasmodium falciparum

Plasmodium species, the causative agent of malaria, rely on glucose for energy supply during blood stage. Inhibition of glucose uptake thus represents a potential strategy for the development of antimalarial drugs. Here, we present the crystal structures of PfHT1, the sole hexose transporter in the genome of Plasmodium species, at resolutions of 2.6 Å in complex with D-glucose and 3.7 Å with a moderately selective inhibitor, C3361. Although both structures exhibit occluded conformations, binding of C3361 induces marked rearrangements that result in an additional pocket. This inhibitor-binding-induced pocket presents an opportunity for the rational design of PfHT1-specific inhibitors. Among our designed C3361 derivatives, several exhibited improved inhibition of PfHT1 and cellular potency against P. falciparum, with excellent selectivity to human GLUT1. These findings serve as a proof of concept for the development of the next-generation antimalarial chemotherapeutics by simultaneously targeting the orthosteric and allosteric sites of PfHT1. [Display omitted] •Crystal structure of glucose-bound PfHT1 was determined at 2.6-Å resolution•Crystal structure of PfHT1 bound to a selective inhibitor, C3361, was elucidated•C3361 binding induces a pocket that can be employed for inhibitor optimization•Rational design yielded more potent selective inhibitors with low cytotoxicity Crystal structures of the Plasmodium hexose transporter PfHT1 informed the rational design of glucose uptake inhibitors to starve out malaria parasites.