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Discovery and Development of Inhibitors of the Plasmodial FNT-Type Lactate Transporter as Novel Antimalarials
Plasmodium spp. malaria parasites in the blood stage draw energy from anaerobic glycolysis when multiplying in erythrocytes. They tap the ample glucose supply of the infected host using the erythrocyte glucose transporter 1, GLUT1, and a hexose transporter, HT, of the parasite’s plasma membrane. Per...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624176/ https://www.ncbi.nlm.nih.gov/pubmed/34832972 http://dx.doi.org/10.3390/ph14111191 |
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author | Nerlich, Cornelius Epalle, Nathan H. Seick, Philip Beitz, Eric |
author_facet | Nerlich, Cornelius Epalle, Nathan H. Seick, Philip Beitz, Eric |
author_sort | Nerlich, Cornelius |
collection | PubMed |
description | Plasmodium spp. malaria parasites in the blood stage draw energy from anaerobic glycolysis when multiplying in erythrocytes. They tap the ample glucose supply of the infected host using the erythrocyte glucose transporter 1, GLUT1, and a hexose transporter, HT, of the parasite’s plasma membrane. Per glucose molecule, two lactate anions and two protons are generated as waste that need to be released rapidly from the parasite to prevent blockage of the energy metabolism and acidification of the cytoplasm. Recently, the missing Plasmodium lactate/H(+) cotransporter was identified as a member of the exclusively microbial formate–nitrite transporter family, FNT. Screening of an antimalarial compound selection with unknown targets led to the discovery of specific and potent FNT-inhibitors, i.e., pentafluoro-3-hydroxy-pent-2-en-1-ones. Here, we summarize the discovery and further development of this novel class of antimalarials, their modes of binding and action, circumvention of a putative resistance mutation of the FNT target protein, and suitability for in vivo studies using animal malaria models. |
format | Online Article Text |
id | pubmed-8624176 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-86241762021-11-27 Discovery and Development of Inhibitors of the Plasmodial FNT-Type Lactate Transporter as Novel Antimalarials Nerlich, Cornelius Epalle, Nathan H. Seick, Philip Beitz, Eric Pharmaceuticals (Basel) Review Plasmodium spp. malaria parasites in the blood stage draw energy from anaerobic glycolysis when multiplying in erythrocytes. They tap the ample glucose supply of the infected host using the erythrocyte glucose transporter 1, GLUT1, and a hexose transporter, HT, of the parasite’s plasma membrane. Per glucose molecule, two lactate anions and two protons are generated as waste that need to be released rapidly from the parasite to prevent blockage of the energy metabolism and acidification of the cytoplasm. Recently, the missing Plasmodium lactate/H(+) cotransporter was identified as a member of the exclusively microbial formate–nitrite transporter family, FNT. Screening of an antimalarial compound selection with unknown targets led to the discovery of specific and potent FNT-inhibitors, i.e., pentafluoro-3-hydroxy-pent-2-en-1-ones. Here, we summarize the discovery and further development of this novel class of antimalarials, their modes of binding and action, circumvention of a putative resistance mutation of the FNT target protein, and suitability for in vivo studies using animal malaria models. MDPI 2021-11-20 /pmc/articles/PMC8624176/ /pubmed/34832972 http://dx.doi.org/10.3390/ph14111191 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Nerlich, Cornelius Epalle, Nathan H. Seick, Philip Beitz, Eric Discovery and Development of Inhibitors of the Plasmodial FNT-Type Lactate Transporter as Novel Antimalarials |
title | Discovery and Development of Inhibitors of the Plasmodial FNT-Type Lactate Transporter as Novel Antimalarials |
title_full | Discovery and Development of Inhibitors of the Plasmodial FNT-Type Lactate Transporter as Novel Antimalarials |
title_fullStr | Discovery and Development of Inhibitors of the Plasmodial FNT-Type Lactate Transporter as Novel Antimalarials |
title_full_unstemmed | Discovery and Development of Inhibitors of the Plasmodial FNT-Type Lactate Transporter as Novel Antimalarials |
title_short | Discovery and Development of Inhibitors of the Plasmodial FNT-Type Lactate Transporter as Novel Antimalarials |
title_sort | discovery and development of inhibitors of the plasmodial fnt-type lactate transporter as novel antimalarials |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624176/ https://www.ncbi.nlm.nih.gov/pubmed/34832972 http://dx.doi.org/10.3390/ph14111191 |
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