Discovery and Development of Inhibitors of the Plasmodial FNT-Type Lactate Transporter as Novel Antimalarials

<i>Plasmodium</i> 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 p...

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Auteurs principaux:	Cornelius Nerlich, Nathan H. Epalle, Philip Seick, Eric Beitz
Format:	article
Langue:	EN
Publié:	MDPI AG 2021
Sujets:	formate–nitrite transporter lactate <i>Plasmodium</i> malaria antimalarials Medicine R Pharmacy and materia medica RS1-441
Accès en ligne:	https://doaj.org/article/bafceb0d7e8341a99b01aa4465180765
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spelling	oai:doaj.org-article:bafceb0d7e8341a99b01aa44651807652021-11-25T18:40:04ZDiscovery and Development of Inhibitors of the Plasmodial FNT-Type Lactate Transporter as Novel Antimalarials10.3390/ph141111911424-8247https://doaj.org/article/bafceb0d7e8341a99b01aa44651807652021-11-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1191https://doaj.org/toc/1424-8247<i>Plasmodium</i> 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 <i>Plasmodium</i> lactate/H<sup>+</sup> 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.Cornelius NerlichNathan H. EpallePhilip SeickEric BeitzMDPI AGarticleformate–nitrite transporterlactate<i>Plasmodium</i>malariaantimalarialsMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1191, p 1191 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	formate–nitrite transporter lactate <i>Plasmodium</i> malaria antimalarials Medicine R Pharmacy and materia medica RS1-441
spellingShingle	formate–nitrite transporter lactate <i>Plasmodium</i> malaria antimalarials Medicine R Pharmacy and materia medica RS1-441 Cornelius Nerlich Nathan H. Epalle Philip Seick Eric Beitz Discovery and Development of Inhibitors of the Plasmodial FNT-Type Lactate Transporter as Novel Antimalarials
description	<i>Plasmodium</i> 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 <i>Plasmodium</i> lactate/H<sup>+</sup> 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	article
author	Cornelius Nerlich Nathan H. Epalle Philip Seick Eric Beitz
author_facet	Cornelius Nerlich Nathan H. Epalle Philip Seick Eric Beitz
author_sort	Cornelius Nerlich
title	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_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_sort	discovery and development of inhibitors of the plasmodial fnt-type lactate transporter as novel antimalarials
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/bafceb0d7e8341a99b01aa4465180765
work_keys_str_mv	AT corneliusnerlich discoveryanddevelopmentofinhibitorsoftheplasmodialfnttypelactatetransporterasnovelantimalarials AT nathanhepalle discoveryanddevelopmentofinhibitorsoftheplasmodialfnttypelactatetransporterasnovelantimalarials AT philipseick discoveryanddevelopmentofinhibitorsoftheplasmodialfnttypelactatetransporterasnovelantimalarials AT ericbeitz discoveryanddevelopmentofinhibitorsoftheplasmodialfnttypelactatetransporterasnovelantimalarials
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Discovery and Development of Inhibitors of the Plasmodial FNT-Type Lactate Transporter as Novel Antimalarials

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