Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti-Malarial Compounds

• Published in: PloS one 2015-04, Vol.10 (4), p.e0123598
• Main Authors: Ortiz, Diana, Guiguemde, W Armand, Johnson, Alex, Elya, Carolyn, Anderson, Johanna, Clark, Julie, Connelly, Michele, Yang, Lei, Min, Jaeki, Sato, Yuko, Guy, R Kiplin, Landfear, Scott M
• Format: Article
• Language: English
• Subjects: Analogs; Animals; Antimalarials - analysis; Antimalarials - pharmacokinetics; Antimalarials - pharmacology; Aquatic insects; Cell Proliferation - drug effects; Drug development; Drug resistance; Drugs; Erythrocytes - drug effects; Erythrocytes - parasitology; Glucose; Glucose - metabolism; Glucose Transporter Type 1 - metabolism; Glycolysis; Hexose; Hexose transporter; High-throughput screening; High-Throughput Screening Assays - methods; Humans; Inhibitors; Kinetics; Leishmania donovani; Libraries; Life cycle engineering; Life cycles; Liver; Malaria; Male; Medical screening; Mice; Monosaccharide Transport Proteins - antagonists & inhibitors; Monosaccharide Transport Proteins - metabolism; Mutants; Parasites; Parasites - drug effects; Permease; Plasmodium falciparum; Plasmodium falciparum - drug effects; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - metabolism; Vector-borne diseases; Viability
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0123598

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.