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 vinylogou...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2017-02-01
|
Series: | PLoS Pathogens |
Online Access: | http://europepmc.org/articles/PMC5298233?pdf=render |
id |
doaj-eee398c1b882486ebd15633f57099ebb |
---|---|
record_format |
Article |
spelling |
doaj-eee398c1b882486ebd15633f57099ebb2020-11-25T01:32:47ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742017-02-01132e100617210.1371/journal.ppat.1006172Substrate-analogous inhibitors exert antimalarial action by targeting the Plasmodium lactate transporter PfFNT at nanomolar scale.André GolldackBjörn HenkeBärbel BergmannMarie WiechertHolger ErlerAlexandra Blancke SoaresTobias SpielmannEric BeitzResistance 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.http://europepmc.org/articles/PMC5298233?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
André Golldack Björn Henke Bärbel Bergmann Marie Wiechert Holger Erler Alexandra Blancke Soares Tobias Spielmann Eric Beitz |
spellingShingle |
André Golldack Björn Henke Bärbel Bergmann Marie Wiechert Holger Erler Alexandra Blancke Soares Tobias Spielmann Eric Beitz Substrate-analogous inhibitors exert antimalarial action by targeting the Plasmodium lactate transporter PfFNT at nanomolar scale. PLoS Pathogens |
author_facet |
André Golldack Björn Henke Bärbel Bergmann Marie Wiechert Holger Erler Alexandra Blancke Soares Tobias Spielmann Eric Beitz |
author_sort |
André Golldack |
title |
Substrate-analogous inhibitors exert antimalarial action by targeting the Plasmodium lactate transporter PfFNT at nanomolar scale. |
title_short |
Substrate-analogous inhibitors exert antimalarial action by targeting the Plasmodium lactate transporter PfFNT at nanomolar scale. |
title_full |
Substrate-analogous inhibitors exert antimalarial action by targeting the Plasmodium lactate transporter PfFNT at nanomolar scale. |
title_fullStr |
Substrate-analogous inhibitors exert antimalarial action by targeting the Plasmodium lactate transporter PfFNT at nanomolar scale. |
title_full_unstemmed |
Substrate-analogous inhibitors exert antimalarial action by targeting the Plasmodium lactate transporter PfFNT at nanomolar scale. |
title_sort |
substrate-analogous inhibitors exert antimalarial action by targeting the plasmodium lactate transporter pffnt at nanomolar scale. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2017-02-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC5298233?pdf=render |
work_keys_str_mv |
AT andregolldack substrateanalogousinhibitorsexertantimalarialactionbytargetingtheplasmodiumlactatetransporterpffntatnanomolarscale AT bjornhenke substrateanalogousinhibitorsexertantimalarialactionbytargetingtheplasmodiumlactatetransporterpffntatnanomolarscale AT barbelbergmann substrateanalogousinhibitorsexertantimalarialactionbytargetingtheplasmodiumlactatetransporterpffntatnanomolarscale AT mariewiechert substrateanalogousinhibitorsexertantimalarialactionbytargetingtheplasmodiumlactatetransporterpffntatnanomolarscale AT holgererler substrateanalogousinhibitorsexertantimalarialactionbytargetingtheplasmodiumlactatetransporterpffntatnanomolarscale AT alexandrablanckesoares substrateanalogousinhibitorsexertantimalarialactionbytargetingtheplasmodiumlactatetransporterpffntatnanomolarscale AT tobiasspielmann substrateanalogousinhibitorsexertantimalarialactionbytargetingtheplasmodiumlactatetransporterpffntatnanomolarscale AT ericbeitz substrateanalogousinhibitorsexertantimalarialactionbytargetingtheplasmodiumlactatetransporterpffntatnanomolarscale |
_version_ |
1725079796964130816 |