Orthosteric–allosteric dual inhibitors of PfHT1 as selective antimalarial agents

Abstract

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.

Selective inhibition of PfATP6 by artemisinins and identification of new classes of inhibitors after expression in yeast

“…In the course of investigating various families of transport proteins we first isolated, functionally characterised in Xenopus oocytes, and genetically validated the parasite's hexose transporter, PfHT, as a new drug target 37 . Co-crystallisation of PfHT with the selective inhibitor we characterised has confirmed that structure-based design of inhibitors against integral membrane proteins of P. falciparum is feasible 38 .…”

Structural characterization of the Plasmodium falciparum lactate transporter PfFNT alone and in complex with antimalarial compound MMV007839 reveals its inhibition mechanism

“…As an essential component of the glucose–lactate transport cycle, PfFNT, together with PfHT1, is vital for the energy supply and metabolic homeostasis of parasites [ 9 , 10 ]. The energy supply of parasites can be cut off by inhibiting glucose uptake, making PfHT1 a valuable drug target for next-generation antimalarial development [ 12 – 14 ]. PfFNT, hence, represents another Achilles’ heel of this transport cycle that can be exploited for chemotherapeutic development of malaria.…”

Discovery and Development of Inhibitors of the Plasmodial FNT-Type Lactate Transporter as Novel Antimalarials

“…D-glucose is taken up via the erythrocyte's glucose transporter, GLUT1 [8,9], and the parasite's hexose transporter, HT [10,11]. The protein structures of the human [12,13] and recently of the plasmodial glucose transporters [14] have been resolved at high resolution. Such transporters are themselves attractive targets for the design of antimalarials [15][16][17].…”

“…Such transporters are themselves attractive targets for the design of antimalarials [15][16][17]. In fact, the HT structure and a human homolog, GLUT3, were elucidated in the presence of an inhibitor, C3361, and the structures were used successfully to optimize the affinity of the small molecule [13,14]. Such compounds exhibit antimalarial activity in parasite cultures by blocking glycolysis via HT-inhibition [13][14][15]17] or by inducing apoptosis via redox stress when acting on the erythrocyte GLUT [16].…”

“…Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 10 of the small molecule [13,14]. Such compounds exhibit antimalarial activity in parasite cultures by blocking glycolysis via HT-inhibition [13][14][15]17] or by inducing apoptosis via redox stress when acting on the erythrocyte GLUT [16].…”