Substrate-analogous inhibitors exert antimalarial action by targeting the Plasmodium lactate transporter PfFNT at nanomolar scale.
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.
Pharmaceutical Institute, Christian-Albrechts-University, Kiel, Germany.
André
A
Golldack
Pharmaceutical Institute, Christian-Albrechts-University, Kiel, Germany.
Björn
B
Henke
Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany.
Bärbel
0000-0002-1869-3533
B
Bergmann
Pharmaceutical Institute, Christian-Albrechts-University, Kiel, Germany.
Marie
M
Wiechert
Pharmaceutical Institute, Christian-Albrechts-University, Kiel, Germany.
Holger
0000-0001-5780-8703
H
Erler
Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany.
Alexandra
A
Blancke Soares
Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany.
Tobias
0000-0002-3968-4601
T
Spielmann
Pharmaceutical Institute, Christian-Albrechts-University, Kiel, Germany.
Eric
0000-0001-5912-6626
E
Beitz
D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D016778:Malaria, Falciparum / Q000378:metabolism*; D027501:Monocarboxylic Acid Transporters / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D015800:Protozoan Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
D000962:Antimalarials; D027501:Monocarboxylic Acid Transporters; D015800:Protozoan Proteins