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Impact of Field Isolate Identified Nonsynonymous Single Nucleotide Polymorphisms on Plasmodium falciparum Equilibrative Nucleoside Transporter 1 Inhibitor Efficacy
journal contribution
posted on 2020-01-13, 13:04 authored by Yvett Sosa, Deborah Egbo, Myles H. AkabasPlasmodium falciparum causes the most severe form of malaria
and causes approximately 500 000 deaths per year. P. falciparum parasites resistant to current antimalarial
treatments are spreading. Therefore, it is imperative to develop new
antimalarial drugs. Malaria parasites are purine auxotrophic. They
rely on purine import from the host erythrocyte via Equilibrative
Nucleoside Transporters (ENTs). Recently, inhibitors of the P. falciparum ENT1 (PfENT1) that inhibit proliferation of
malaria parasites in culture have been identified as promising starting
points for antimalarial drug development. Genome sequencing of P. falciparum field isolates has identified nonsynonymous
single nucleotide polymorphisms (SNPs) in the gene encoding PfENT1.
Here we evaluate the impact of these PfENT1 SNPs on purine substrate
affinity and inhibitor efficacy. We expressed each PfENT1-SNP in Saccharomyces cerevisiae. Using PfENT1-SNP-expressing yeast,
we characterized the PfENT1 purine substrate affinity using radiolabeled
substrate uptake inhibition experiments. Four of the 13 SNPs altered
affinity for one or more purines by up to 7-fold. Three of the SNPs
reduced the potency of a subset of the inhibitors by up to 7-fold.
One SNP, Q284E, reduced the potency of all six inhibitor chemotypes.
We tested drug efficacy in available parasite strains containing PfENT1
SNPs. While PfENT1-SNP-expressing yeast had decreased sensitivity
to PfENT1 inhibitors, parasite strains containing SNPs showed similar
or more potent inhibition of proliferation with all PfENT1 inhibitors.
Thus, parasite strains bearing PfENT1 SNPs are not resistant to these
PfENT1 inhibitors. This supports PfENT1 as a promising target for
further development of novel antimalarial drugs.
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Equilibrative Nucleoside TransportersField Isolate Identified Nonsynonymous Single Nucleotide Polymorphisms500 000 deathsPfENT 1 purine substrate affinityPfENT 1 SNPsPfENT 1 inhibitorsparasite strainsnovel antimalarial drugsfalciparum ENT 1284EPlasmodium falciparum Equilibrative Nucleoside Transporter 1 Inhibitor Efficacy Plasmodium falciparum causesradiolabeled substrate uptake inhibition experimentsantimalarial drug developmentgene encoding PfENT 1.PfENT 1-SNP yeastpurine substrate affinity
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