Substrate-analogous inhibitors exert antimalarial action by targeting the Plasmodium lactate transporter PfFNT at nanomolar scale

PLoS Pathogens

Bärbel Bergmann¹  Tobias Spielmann¹  Alexandra Blancke Soares¹  Björn Henke²  Holger Erler²  Eric Beitz²  Marie Wiechert²  André Golldack² 

[1] Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany;Pharmaceutical Institute, Christian-Albrechts-University, Kiel, Germany

关键词: Malarial parasites;    Malaria;    Antimalarials;    Antimicrobial resistance;    Pro-drugs;    Yeast;    Plasmodium;    Lactates;   

DOI  :  10.1371/journal.ppat.1006172

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Resistance against all available antimalarial drugs calls for novel compounds that hit unexploited targets in the parasite. Here, we show that the recently discovered Plasmodium falciparum lactate/proton symporter, PfFNT, is a valid druggable target, and describe a new class of fluoroalkyl vinylogous acids that potently block PfFNT and kill cultured parasites. The original compound, MMV007839, is derived from the malaria box collection of potent antimalarials with unknown targets and contains a unique internal prodrug principle that reversibly switches between a lipophilic transport form and a polar, substrate-analogous active form. Resistance selection of cultured P. falciparum parasites with sub-lethal concentrations of MMV007839 produced a single nucleotide exchange in the PfFNT gene; this, and functional characterization of the resulting PfFNT G107S validated PfFNT as a novel antimalarial target. From quantitative structure function relations we established the compound binding mode and the pharmacophore. The pharmacophore largely circumvents the resistance mutation and provides the basis for a medicinal chemistry program that targets lactate and proton transport as a new mode of antimalarial action.

【 授权许可】

CC BY