The inhibitory effect of 2-halo derivatives of D-glucose on glycolysis and on the proliferation of the human malaria parasite Plasmodium falciparum.
The intraerythrocytic stage of the human malaria parasite Plasmodium falciparum relies on glycolysis for ATP generation, and because it has no energy stores, a constant supply of glucose is necessary for the parasite to grow and multiply. The 2-substituted glucose analogs 2-deoxy-D-glucose (2-DG) and 2-fluoro-2-deoxy-D-glucose (2-FG) have been previously shown to inhibit the in vitro growth of P. falciparum and have been suggested to do so by inhibiting glycosylation in the parasite. In this study, we have investigated the antiplasmodial mechanism of action of 2-DG and 2-FG and compared it with that of other 2-substituted-glucose analogs. The compounds tested inhibited parasite growth to varying degrees, with 2-FG being the most effective. The antiplasmodial activity of some, but not all, of the analogs could be altered by varying the glucose concentration in the culture medium, increasing the antiplasmodial activity of the analogs as the glucose concentration is reduced. A trend was observed between the antiplasmodial activity of these analogs and their ability to inhibit glucose accumulation, glucose phosphorylation by hexokinase, and cytosolic pH regulation within the intraerythrocytic stage of the parasite. Our data are consistent with inhibition of glycolysis being a primary mechanism by which 2-DG and 2-FG inhibit parasite growth, and they validate the early steps in glycolysis as viable drug targets.
van Schalkwyk
Donelly A
DA
School of Biochemistry and Molecular Biology, The Australian National University, Canberra, ACT, Australia.
Priebe
Waldemar
W
Saliba
Kevin J
KJ
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology; D003847:Deoxyglucose / Q000493:pharmacokinetics / Q000494:pharmacology; D019788:Fluorodeoxyglucose F18 / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D010766:Phosphorylation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism
D000962:Antimalarials; D037621:Artemisinins; D019788:Fluorodeoxyglucose F18; D002738:Chloroquine; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; C031327:artemisinin