title: Use of a selective inhibitor to define the chemotherapeutic potential of the plasmodial hexose transporter in different stages of the parasite's life cycle.
abstract: During blood infection, malarial parasites use D-glucose as their main energy source. The Plasmodium falciparum hexose transporter (PfHT), which mediates the uptake of D-glucose into parasites, is essential for survival of asexual blood-stage parasites. Recently, genetic studies in the rodent malaria model, Plasmodium berghei, found that the orthologous hexose transporter (PbHT) is expressed throughout the parasite's development within the mosquito vector, in addition to being essential during intraerythrocytic development. Here, using a D-glucose-derived specific inhibitor of plasmodial hexose transporters, compound 3361, we have investigated the importance of D-glucose uptake during liver and transmission stages of P. berghei. Initially, we confirmed the expression of PbHT during liver stage development, using a green fluorescent protein (GFP) tagging strategy. Compound 3361 inhibited liver-stage parasite development, with a 50% inhibitory concentration (IC₅₀) of 11 μM. This process was insensitive to the external D-glucose concentration. In addition, compound 3361 inhibited ookinete development and microgametogenesis, with IC₅₀s in the region of 250 μM (the latter in a D-glucose-sensitive manner). Consistent with our findings for the effect of compound 3361 on vector parasite stages, 1 mM compound 3361 demonstrated transmission blocking activity. These data indicate that novel chemotherapeutic interventions that target PfHT may be active against liver and, to a lesser extent, transmission stages, in addition to blood stages.
authors.affiliation: Centre for Infection and Immunity, Division of Clinical Sciences, St. George's, University of London, London SW170RE, United Kingdom.
authors.forename: Ksenija
authors.initials: K
authors.lastname: Slavic
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Delves
authors.forename: Miguel
authors.initials: M
authors.lastname: Prudêncio
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Talman
authors.forename: Ursula
authors.initials: U
authors.lastname: Straschil
authors.forename: Elvira T
authors.initials: ET
authors.lastname: Derbyshire
authors.forename: Zhengyao
authors.initials: Z
authors.lastname: Xu
authors.forename: Robert E
authors.initials: RE
authors.lastname: Sinden
authors.forename: Maria M
authors.initials: MM
authors.lastname: Mota
authors.forename: Christophe
authors.initials: C
authors.lastname: Morin
authors.forename: Rita
authors.initials: R
authors.lastname: Tewari
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Krishna
authors.forename: Henry M
authors.initials: HM
authors.lastname: Staines
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004912:Erythrocytes / Q000469:parasitology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000469:parasitology; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors*; D010962:Plasmodium berghei / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000962:Antimalarials; D009004:Monosaccharide Transport Proteins; D005947:Glucose