Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti-Malarial Compounds.
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 glycolyt...
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2015-01-01
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doaj-3157b6287d2b423eb876d7995bd2c64e2020-11-25T00:02:11ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01104e012359810.1371/journal.pone.0123598Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti-Malarial Compounds.Diana OrtizW Armand GuiguemdeAlex JohnsonCarolyn ElyaJohanna AndersonJulie ClarkMichele ConnellyLei YangJaeki MinYuko SatoR Kiplin GuyScott M LandfearDevelopment 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.http://europepmc.org/articles/PMC4404333?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti-Malarial Compounds. PLoS ONE |
author_facet |
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 |
author_sort |
Diana Ortiz |
title |
Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti-Malarial Compounds. |
title_short |
Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti-Malarial Compounds. |
title_full |
Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti-Malarial Compounds. |
title_fullStr |
Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti-Malarial Compounds. |
title_full_unstemmed |
Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti-Malarial Compounds. |
title_sort |
identification of selective inhibitors of the plasmodium falciparum hexose transporter pfht by screening focused libraries of anti-malarial compounds. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2015-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC4404333?pdf=render |
work_keys_str_mv |
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