title: Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti-Malarial Compounds.
abstract: Development of resistance against current antimalarial drugs necessitates the search for novel drugs that interact with different targets and have distinct mechanisms of action. Malaria parasites depend upon high levels of glucose uptake followed by inefficient metabolic utilization via the glycolytic pathway, and the Plasmodium falciparum hexose transporter PfHT, which mediates uptake of glucose, has thus been recognized as a promising drug target. This transporter is highly divergent from mammalian hexose transporters, and it appears to be a permease that is essential for parasite viability in intra-erythrocytic, mosquito, and liver stages of the parasite life cycle. An assay was developed that is appropriate for high throughput screening against PfHT based upon heterologous expression of PfHT in Leishmania mexicana parasites that are null mutants for their endogenous hexose transporters. Screening of two focused libraries of antimalarial compounds identified two such compounds that are high potency selective inhibitors of PfHT compared to human GLUT1. Additionally, 7 other compounds were identified that are lower potency and lower specificity PfHT inhibitors but might nonetheless serve as starting points for identification of analogs with more selective properties. These results further support the potential of PfHT as a novel drug target.
authors.affiliation: Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR, United States of America.
authors.forename: Diana
authors.initials: D
authors.lastname: Ortiz
authors.affiliation: Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, United States of America.
authors.forename: W Armand
authors.initials: WA
authors.lastname: Guiguemde
authors.affiliation: Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR, United States of America.
authors.forename: Alex
authors.initials: A
authors.lastname: Johnson
authors.affiliation: Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR, United States of America.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Elya
authors.affiliation: Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR, United States of America.
authors.forename: Johanna
authors.initials: J
authors.lastname: Anderson
authors.affiliation: Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, United States of America.
authors.forename: Julie
authors.initials: J
authors.lastname: Clark
authors.affiliation: Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, United States of America.
authors.forename: Michele
authors.initials: M
authors.lastname: Connelly
authors.affiliation: Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, United States of America.
authors.forename: Jaeki
authors.initials: J
authors.lastname: Min
authors.affiliation: Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR, United States of America.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN, United States of America.
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.affiliation: Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR, United States of America.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Landfear
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000032:analysis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010271:Parasites / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000962:Antimalarials; D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; D015800:Protozoan Proteins; D005947:Glucose