Identification of selective inhibitors of the Plasmodium falciparum hexose transporter PfHT by screening focused libraries of anti-malarial compounds

Diana Ortiz, W. Armand Guiguemde, Alex Johnson, Carolyn Elya, Johanna Anderson, Julie Clark, Michele Connelly, Lei Yang, Jaeki Min, Yuko Sato, R. Kiplin Guy, Scott M. Landfear

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Article numbere0123598
JournalPLoS One
Volume10
Issue number4
DOIs
Publication statusPublished - 2015 Apr 20
Externally publishedYes

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Monosaccharide Transport Proteins
antimalarials
Antimalarials
Plasmodium falciparum
hexoses
transporters
Screening
Parasites
screening
parasites
drugs
Leishmania mexicana
Pharmaceutical Preparations
uptake mechanisms
Glucose
glucose
Membrane Transport Proteins
glycolysis
Life Cycle Stages
Culicidae

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Identification of selective inhibitors of the Plasmodium falciparum hexose transporter PfHT by screening focused libraries of anti-malarial compounds. / 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.

In: PLoS One, Vol. 10, No. 4, e0123598, 20.04.2015.

Research output: Contribution to journalArticle

Ortiz, D, Guiguemde, WA, Johnson, A, Elya, C, Anderson, J, Clark, J, Connelly, M, Yang, L, Min, J, Sato, Y, Guy, RK & Landfear, SM 2015, 'Identification of selective inhibitors of the Plasmodium falciparum hexose transporter PfHT by screening focused libraries of anti-malarial compounds', PLoS One, vol. 10, no. 4, e0123598. https://doi.org/10.1371/journal.pone.0123598
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. / Identification of selective inhibitors of the Plasmodium falciparum hexose transporter PfHT by screening focused libraries of anti-malarial compounds. In: PLoS One. 2015 ; Vol. 10, No. 4.
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