Artemisinin-resistant malaria parasites have emerged and have been spreading, posing a significant public health challenge. Antimalarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a “selective starvation” strategy by inhibiting Plasmodium falciparum hexose transporter 1 (PfHT1), the sole hexose transporter in P. falciparum, over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-resistant malaria parasites. The crystal structure of hGLUT3, which shares 80% sequence similarity with hGLUT1, was resolved in complex with C3361, a moderate PfHT1-specific inhibitor, at 2.3-Å resolution. Structural comparison between the present hGLUT3-C3361 and our previously reported PfHT1-C3361 confirmed the unique inhibitor binding-induced pocket in PfHT1. We then designed small molecules to simultaneously block the orthosteric and allosteric pockets of PfHT1. Through extensive structure–activity relationship studies, the TH-PF series was identified to selectively inhibit PfHT1 over hGLUT1 and potent against multiple strains of the blood-stage P. falciparum. Our findings shed light on the next-generation chemotherapeutics with a paradigm-shifting structure-based design strategy to simultaneously target the orthosteric and allosteric sites of a transporter.

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Flowering is the first committed step of plant sexual reproduction. While the developing flower is a strong sink requiring large quantity of sugars from photosynthetic source tissues, this process is under-temper-spatially controlled via hormone signaling pathway and nutrient availability. Sugar transporters SUT/SUC and SWEET mediate sugars movement across membranes and play a significant role in various physiological processes, including reproductive organ development. In Petunia axillaris, a model ornamental plant, 5 SUT/SUC and 36 SWEET genes are identified in the current version of the genome. Analysis of their gene structure and chromosomal locations reveal that SWEET family is moderately expanded. Most of the transporter genes are abundantly expressed in the flower than in other organs. During the five flower developmental stages, transcript levels of PaSUT1, PaSUT3, PaSWEET13c, PaSWEET9a, PaSWEET1d, PaSWEET5a and PaSWEET14a increase with the maturation of the flower and reach their maximum in the fully open flowers. PaSWEET9c, the nectar-specific PhNEC1 orthologous, is expressed in matured and fully opened flowers. Moreover, determination of sugar concentrations and phytohormone dynamics in flowers at the five developmental stages shows that glucose is the predominant form of sugar in young flowers at the early stage but depletes at the later stage, whereas sucrose accumulates only in maturated flowers prior to the corolla opening. On the other hand, GA3 content and to a less extent IAA and zeatin decreases with the flower development; however, JA, SA and ABA display a remarkable peak at mid- or later flower developmental stage.