Abstract
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.
Highlights
Malaria remains one of the most prevalent human parasitic diseases, being responsible for 229 million recorded infections and 409,000 deaths in 2019, mainly of children under the age of five [1]
The most severe and widespread form of cerebral malaria is caused by Plasmodium falciparum
Despite encouraging results toward vaccination, disease control, and eradication, resistance of Plasmodium spp. parasites to antimalarial drugs is on the rise, stressing the need to widen our therapeutic arsenal with new drugs [2,3]
Summary
Malaria remains one of the most prevalent human parasitic diseases, being responsible for 229 million recorded infections and 409,000 deaths in 2019, mainly of children under the age of five [1]. The HT structure and a human homolog, GLUT3, were elucidated in the presence of an inhibitor, C3361, and the structures were used successfully to optimize the affinity of the small molecule [13,14] Glycolysis generates from glucose, forming the metabolic and protons that and protons that are exported via into the erythrocyte cytosol, and eventually by the human are exported via PfFNT into the erythrocyte cytosol, and eventually by the human monocarboxylate monocarboxylate transporter, MCT1, or alternative red cell export pathways. Type protein the missing lactate/proton co-transporter the parasites [18, The microbial. Withthe thediscovery discoveryofofPfFNT, PfFNT, the the transport transport components of the malaria parasite’s energy flux were complete
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