title: The Glucose Transporter PfHT1 Is an Antimalarial Target of the HIV Protease Inhibitor Lopinavir.
abstract: Malaria and HIV infection are coendemic in a large portion of the world and remain a major cause of morbidity and mortality. Growing resistance of Plasmodium species to existing therapies has increased the need for new therapeutic approaches. The Plasmodium glucose transporter PfHT is known to be essential for parasite growth and survival. We have previously shown that HIV protease inhibitors (PIs) act as antagonists of mammalian glucose transporters. While the PI lopinavir is known to have antimalarial activity, the mechanism of action is unknown. We report here that lopinavir blocks glucose uptake into isolated malaria parasites at therapeutically relevant drug levels. Malaria parasites depend on a constant supply of glucose as their primary source of energy, and decreasing the available concentration of glucose leads to parasite death. We identified the malarial glucose transporter PfHT as a target for inhibition by lopinavir that leads to parasite death. This discovery provides a mechanistic basis for the antimalarial effect of lopinavir and provides a direct target for novel drug design with utility beyond the HIV-infected population.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Kraft
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Armstrong
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Monique R
authors.initials: MR
authors.lastname: Heitmeier
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Audrey R
authors.initials: AR
authors.lastname: Odom
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA hruz_p@kids.wustl.edu.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Hruz
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D001692:Biological Transport; D058492:Drug Repositioning; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D015870:Gene Expression; D005947:Glucose / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057809:HEK293 Cells; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D061466:Lopinavir / Q000737:chemistry / Q000494:pharmacology*; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D017320:HIV Protease Inhibitors; D009004:Monosaccharide Transport Proteins; D015800:Protozoan Proteins; D011994:Recombinant Proteins; C118145:hexose transporter 1 protein, Plasmodium falciparum; D061466:Lopinavir; D005947:Glucose