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NOT Open Access | Structural basis of transport and inhibition of the Plasmodium falciparum transporter PfFNT

January 21, 2021 - 15:33 -- NOT Open Access
Lyu M, Su CC, Kazura JW, Yu EW
EMBO Rep. 2021 Jan 20:e51628

The intra-erythrocyte stage of P. falciparum relies primarily on glycolysis to generate adenosine triphosphate (ATP) and the energy required to support growth and reproduction. Lactic acid, a metabolic byproduct of glycolysis, is potentially toxic as it lowers the pH inside the parasite. Plasmodium falciparum formate-nitrite transporter (PfFNT), a 34-kDa transmembrane protein, has been identified as a novel drug target as it exports lactate from inside the parasite to the surrounding parasitophorous vacuole within the erythrocyte cytosol.

Pentafluoro-3-hydroxy-pent-2-en-1-ones potently inhibit FNT-type lactate transporters from all five human-pathogenic Plasmodium species

December 23, 2020 - 09:21 -- Open Access
Walloch P, Hansen C, Priegann T, Schade D, Beitz E
ChemMedChem. 2020 Dec 18

The protozoan parasite Plasmodium falciparum causes the most severe and prevailing form of malaria in sub-Saharan Africa. Previously, we identified the plasmodial lactate transporter, PfFNT, a member of the microbial formate-nitrite transporter family, as a novel antimalarial drug target. With the pentafluoro-3-hydroxy-pent-2-en-1-ones, we discovered PfFNT inhibitors that potently kill P. falciparum parasites in vitro.

NOT Open Access | Introduction of scaffold nitrogen atoms renders inhibitors of the malarial L-lactate transporter, PfFNT, effective against the Gly107Ser resistance mutation

August 24, 2020 - 13:19 -- NOT Open Access
Walloch P, Henke B, Häuer S, Bergmann B, Spielmann T, Beitz E
J Med Chem. 2020 Aug 20

The spreading of malaria parasites, Plasmodium falciparum, with resistance to all known drugs calls for novel classes of inhibitors with new modes of action. Recently, we discovered and validated the plasmodial L-lactate transporter, PfFNT, as a novel antimalarial drug target. However, treatment of parasites with a screening hit from the malaria box compound collection, MMV007839, gave rise to a PfFNT Gly107Ser resistance mutation decreasing inhibitor affinity by two orders of magnitude.

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