Plasmodial sugar transporters as anti-malarial drug targets and comparisons with other protozoa

Abstract

Glucose is the primary source of energy and a key substrate for most cells. Inhibition of cellular glucose uptake (the first step in its utilization) has, therefore, received attention as a potential therapeutic strategy to treat various unrelated diseases including malaria and cancers. For malaria, blood forms of parasites rely almost entirely on glycolysis for energy production and, without energy stores, they are dependent on the constant uptake of glucose. Plasmodium falciparum is the most dangerous human malarial parasite and its hexose transporter has been identified as being the major glucose transporter. In this review, recent progress regarding the validation and development of the P. falciparum hexose transporter as a drug target is described, highlighting the importance of robust target validation through both chemical and genetic methods. Therapeutic targeting potential of hexose transporters of other protozoan pathogens is also reviewed and discussed.

Figure 1

Schematic representation of transport processes involved in uptake of hexoses in Plasmodium-infected erythrocytes (A) and predicted topology of PfHT (B). EPM, erythrocyte plasma membrane; PVM, parasitophorous vacuole membrane; PPM, parasite plasma membrane; GLUT1, mammalian glucose transporter; GLUT5, mammalian fructose transporter; NPP, new permeability pathways (do not contribute significantly to the uptake of glucose [62]). B. Predicted topology of PfHT [18].

Figure 2

Structures of the glucose-derived PfHT inhibitors. A. 3-O-(undec-10-en)-1-yl-D-glucose (Compound 3361); B. 2-O-(undec-10-en)-1-yl-D-glucose.

Figure 3

Direct fluorescence imaging of transgenic Plasmodium berghei parasites expressing Plasmodium berghei hexose transporter (PbHT) fused to a GFP protein. a) an oocyst formed inside a mosquito midgut (21 days post infection) containing several hundreds of newly formed sporozoites [39]; b) exoerythocytic schizont formed inside a human hepatoma (Huh-7) cell 67 hours post-infection [41]. Note that the pattern of staining is consistent with localization of PbHT to the parasite plasma membrane, which invaginates around clusters of nuclei during the formation of merozoites. GFP, pbht-gfp P. berghei; HOE, Hoechst 33342 (used as a nuclear dye); BF, bright-field image.

Figure 4

Schematic representation of the life cycle of Plasmodium parasites showing a summary of inhibition and expression studies of plasmodial hexose transporters. Parasites shown in green represent a pbht-gfp transgenic line, which has been analysed via direct fluorescence imaging. Using this transgenic line, expression of PbHT-GFP was observed at 24, 48 and 67 h post infection in the liver stage [41], in both early and late asexual blood stages, in sexual blood stage forms (gametocytes) and in female gametes/or zygotes, ookinetes, midgut oocysts and sporozoites derived from mosquito midgut oocysts and salivary glands [39]. Highlighted life cycle stages (blue boxes) show where compound 3361 inhibits parasite growth and development; in the liver stages in vitro, P. berghei parasite growth is inhibited by compound 3361 with an IC₅₀ value of 11 μM [41]; in the asexual blood stages in vitro, P. falciparum parasite growth is inhibited by compound 3361 with an IC₅₀ value of 16 μM and in vivo P. berghei parasite growth is reduced by 40% (4-day suppression test; 25 mg/kg; administered i.p. twice daily) [30]; in P. berghei sexual stages male gametogenesis (IC₅₀ value of 286 μM) and ookinete production (IC₅₀ value of 252 μM) are inhibited by compound 3361 [41].