Pentafluoro-3-hydroxy-pent-2-en-1-ones Potently Inhibit FNT-Type Lactate Transporters from all Five Human-Pathogenic Plasmodium Species.
antimalarials
formate-nitrite transporter
lactate
malaria
phenotypic assay
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
20 04 2021
20 04 2021
Historique:
received:
10
12
2020
pubmed:
19
12
2020
medline:
12
1
2022
entrez:
18
12
2020
Statut:
ppublish
Résumé
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. Four additional human-pathogenic Plasmodium species require attention, that is, P. vivax, most prevalent outside of Africa, and the regional P. malariae, P. ovale and P. knowlesi. Herein, we show that the plasmodial FNT variants are highly similar in terms of protein sequence and functionality. The FNTs from all human-pathogenic plasmodia and the rodent malaria parasite were efficiently inhibited by pentafluoro-3-hydroxy-pent-2-en-1-ones. We further established a phenotypic yeast-based FNT inhibitor screen, and found very low compound cytotoxicity and monocarboxylate transporter 1 off-target activity on human cells, particularly of the most potent FNT inhibitor BH267.meta, allowing these compounds to proceed towards animal model malaria studies.
Identifiants
pubmed: 33336890
doi: 10.1002/cmdc.202000952
pmc: PMC8247949
doi:
Substances chimiques
Antimalarials
0
Monocarboxylic Acid Transporters
0
Pentanones
0
Protozoan Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1283-1289Subventions
Organisme : M. Casal
Informations de copyright
© 2020 The Authors. ChemMedChem published by Wiley-VCH GmbH.
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