Substrate and Inhibitor Specificity of the<i>Plasmodium berghei</i>Equilibrative Nucleoside Transporter Type 1

Arora, Avish; Deniskin, Roman; Sosa, Yvett; Nishtala, Sita Nirupama; Henrich, Philipp P.; Kumar, T. R. Santha; Fidock, David A.; Akabas, Myles H.

doi:10.1124/mol.115.101386

Cited by 9 publications

(13 citation statements)

References 33 publications

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“…9001893 and 8946464 (Table 2 ), that inhibited the P. falciparum PfENT1 with IC 50 values in the low nanomolar range. Efficiency was similar with the P. vivax and P. berghei ENT1 proteins (Arora et al, 2016 ; Deniskin et al, 2016 ). The compounds were less potent, however, in parasite cultures with EC 50 -values from 0.8 to 6.5 μM (Frame et al, 2015b ).…”

Section: Targeting Transport Processes Of Parasites At Different Levementioning

confidence: 60%

Targeting Channels and Transporters in Protozoan Parasite Infections

2018

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Infectious diseases caused by pathogenic protozoa are among the most significant causes of death in humans. Therapeutic options are scarce and massively challenged by the emergence of resistant parasite strains. Many of the current anti-parasite drugs target soluble enzymes, generate unspecific oxidative stress, or act by an unresolved mechanism within the parasite. In recent years, collections of drug-like compounds derived from large-scale phenotypic screenings, such as the malaria or pathogen box, have been made available to researchers free of charge boosting the identification of novel promising targets. Remarkably, several of the compound hits have been found to inhibit membrane proteins at the periphery of the parasites, i.e., channels and transporters for ions and metabolites. In this review, we will focus on the progress made on targeting channels and transporters at different levels and the potential for use against infections with apicomplexan parasites mainly Plasmodium spp. (malaria) and Toxoplasma gondii (toxoplasmosis), with kinetoplastids Trypanosoma brucei (sleeping sickness), Trypanosoma cruzi (Chagas disease), and Leishmania ssp. (leishmaniasis), and the amoeba Entamoeba histolytica (amoebiasis).

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Section: Targeting Transport Processes Of Parasites At Different Levementioning

confidence: 60%

Targeting Channels and Transporters in Protozoan Parasite Infections

2018

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“…We also tested the efficacies of the compounds on the homologous ENT1 transporters PvENT1 from P. vivax , the most common cause of human malaria, and PbENT1 from P. berghei , a widely used mouse malaria model. PvENT1 and PbENT1 have amino acid sequences 75 and 60% identical, respectively, to that of PfENT1. , PvENT1 and PbENT1 were expressed in the same purine auxotrophic yeast background as PfENT1. For five of the compounds, the IC 50 values for inhibition of [ 3 H]adenosine uptake were within a factor of 2 of the values obtained with PfENT1-expressing yeast.…”

Section: Resultsmentioning

confidence: 99%

“…We examined whether the six PfENT1 inhibitors affected the human RBC purine transporters. To assess the effects of the six compounds on these transporters, we measured the concentration dependent inhibition of (1) [ 3 H]adenosine uptake into RBC to determine interactions with hENT1 and (2) [ 3 H]hypoxanthine uptake into RBC to determine interactions with hFNT, using assays described previously …”

Section: Resultsmentioning

confidence: 99%

Identification via a Parallel Hit Progression Strategy of Improved Small Molecule Inhibitors of the Malaria Purine Uptake Transporter that Inhibit Plasmodium falciparum Parasite Proliferation

et al. 2019

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Emerging resistance to current antimalarial medicines underscores the importance of identifying new drug targets and novel compounds. Malaria parasites are purine auxotrophic and import purines via the Plasmodium falciparum equilibrative nucleoside transporter type 1 (PfENT1). We previously showed that PfENT1 inhibitors block parasite proliferation in culture. Our goal was to identify additional, possibly more optimal chemical starting points for a drug discovery campaign. We performed a high throughput screen (HTS) of GlaxoSmithKline's 1.8 million compound library with a yeast-based assay to identify PfENT1 inhibitors. We used a parallel progression strategy for hit validation and expansion, with an emphasis on chemical properties in addition to potency. In one arm, the most active hits were tested for human cell toxicity; 201 had minimal toxicity. The second arm, hit expansion, used a scaffold-based substructure search with the HTS hits as templates to identify over 2000 compounds; 123 compounds had activity. Of these 324 compounds, 175 compounds inhibited proliferation of P. falciparum parasite strain 3D7 with IC 50 values between 0.8 and ∼180 μM. One hundred forty-two compounds inhibited PfENT1 knockout (pfent1Δ) parasite growth, indicating they also hit secondary targets. Thirty-two hits inhibited growth of 3D7 but not pfent1Δ parasites. Thus, PfENT1 inhibition was sufficient to block parasite proliferation. Therefore, PfENT1 may be a viable target for antimalarial drug development. Six compounds with novel chemical scaffolds were extensively characterized in yeast-, parasite-, and human-erythrocyte-based assays. The inhibitors showed similar potencies against drug sensitive and resistant P. falciparum strains. They represent attractive starting points for development of novel antimalarial drugs.

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“…36 The substrate and inhibitor specificity of P. berghei ENT1 has been reported recently. 37 2.2.2. HGXPRT.…”

Section: Nucleic Acid Metabolism In Plasmodium Falciparummentioning

confidence: 99%

Plasmodium Purine Metabolism and Its Inhibition by Nucleoside and Nucleotide Analogues

et al. 2019

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Malaria still affects around 200 million people and is responsible for more than 400,000 deaths per year, mostly children in subequatorial areas. This disease is caused by parasites of the Plasmodium genus. Only a few WHO-recommended treatments are available to prevent or cure plasmodial infections, but genetic mutations in the causal parasites have led to onset of resistance against all commercial antimalarial drugs. New drugs and targets are being investigated to cope with this emerging problem, including enzymes belonging to the main metabolic pathways, while nucleoside and nucleotide analogues are also a promising class of potential drugs. This review highlights the main metabolic pathways targeted for the development of potential antiplasmodial therapies based on nucleos(t)ide analogues, as well as the different series of purine-containing nucleoside and nucleotide derivatives designed to inhibit Plasmodium falciparum purine metabolism.

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Substrate and Inhibitor Specificity of thePlasmodium bergheiEquilibrative Nucleoside Transporter Type 1

Cited by 9 publications

References 33 publications

Targeting Channels and Transporters in Protozoan Parasite Infections

Targeting Channels and Transporters in Protozoan Parasite Infections

Identification via a Parallel Hit Progression Strategy of Improved Small Molecule Inhibitors of the Malaria Purine Uptake Transporter that Inhibit Plasmodium falciparum Parasite Proliferation

Plasmodium Purine Metabolism and Its Inhibition by Nucleoside and Nucleotide Analogues

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