Targeting the Plasmodium vivax equilibrative nucleoside transporter 1 (PvENT1) for antimalarial drug development

Deniskin, Roman; Frame, Ithiel J.; Sosa, Yvett; Akabas, Myles H.

doi:10.1016/j.ijpddr.2015.11.003

Cited by 16 publications

(22 citation statements)

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“…They kill P. falciparum parasites in culture with 5-to 50-mM IC 50 values. Furthermore, the compounds inhibit the P. vivax equilibrative nucleoside transporter 1 (PvENT1) transporter and PvENT1 nonsynonymous single nucleotide polymorphic variants identified in field isolates (Deniskin et al, 2015). Collectively, these findings support the hypothesis that PfENT1 inhibitors may be developed into novel antimalarial drugs.…”

Section: Introductionsupporting

confidence: 56%

“…To establish the feasibility of using the mouse model, we characterized the functional properties of PbENT1 and determined whether the best hits from our HTS for PfENT1 inhibitors would also work on the P. berghei homolog, PbENT1. PbENT1, like its homologs in P. falciparum and P. vivax (Riegelhaupt et al, 2010;Deniskin et al, 2015), transports both purines and pyrimidines ( Fig. 2; Table 1).…”

Section: Discussionmentioning

confidence: 99%

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Substrate and Inhibitor Specificity of thePlasmodium bergheiEquilibrative Nucleoside Transporter Type 1

et al. 2016

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Malaria is a critical public health issue in the tropical world, causing extensive morbidity and mortality. Infection by unicellular, obligate intracellular Plasmodium parasites causes malaria. The emergence of resistance to current antimalarial drugs necessitates the development of novel therapeutics. A potential novel drug target is the purine import transporter. Because Plasmodium parasites are purine auxotrophic, they must import purines from their host to fulfill metabolic requirements. They import purines via equilibrative nucleoside transporter 1 (ENT1) homologs. Recently, we used a yeast-based high-throughput screen to identify inhibitors of the P. falciparum ENT1 (PfENT1) that kill P. falciparum parasites in culture. P. berghei infection of mice is an animal model for human malaria. Because P. berghei ENT1 (PbENT1) shares only 60% amino acid sequence identity with PfENT1, we sought to characterize PbENT1 and its sensitivity to our PfENT1 inhibitors. We expressed PbENT1 in purine auxotrophic yeast and used radiolabeled substrate uptake to characterize its function. We showed that PbENT1 transports both purines and pyrimidines. It preferred nucleosides compared with nucleobases. Inosine (IC 50 5 3.7 mM) and guanosine (IC 50 5 21.3 mM) had the highest affinities. Our recently discovered PfENT1 inhibitors were equally effective against both PbENT1-and PfENT1-mediated purine uptake. The PfENT1 inhibitors are at least 10-fold more potent against PfENT1 than human hENT1. They kill P. berghei parasites in 24-hour ex vivo culture. Thus, the P. berghei murine malaria model may be useful to evaluate the efficacy of PfENT1 inhibitors in vivo and their therapeutic potential for treatment of malaria.

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Section: Introductionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Substrate and Inhibitor Specificity of thePlasmodium bergheiEquilibrative Nucleoside Transporter Type 1

et al. 2016

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“…Similar scaffolds ( 485 – 487 ) have been reported as inhibitors of fungal nucleobase transporter (FcyB) as well as the human NK 3 tachykinin receptor ( 488 ) . Inhibition of nucleobase transport, which prevents the salvage of purines, has been demonstrated as a viable target for antimalarial drug discovery, with Akbas and co‐workers developing a cohort of compounds (e.g., 489 ) capable of inhibiting P. falciparum equilibrative nucleoside transporter type 1 ( Pf ENT1) . The antiprion benzoxazole MMV007920 ( 490 ) from the Pathogen Box closely resembles the structure of 489 , which may account for its antiplasmodial activity.…”

Section: Malariamentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.

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“…An attempt to express PfATP6 in a mammalian cell line was likewise unsuccessful (Cardi et al ., ), and mammalian cell lines also proved largely unsuitable for the expression and characterisation of PfCRT and PfMDR1 – in both cases the transporters were trapped on intracellular membranes (van Es et al ., ; Reeves et al ., ). Functional expression of PfATP6 was ultimately achieved in a yeast expression system (Cardi et al ., ) and several other Plasmodium transporters have likewise been expressed and characterised (to varying degrees) in yeast heterologous systems – those studied in detail include PfCAX (Salcedo‐Sora, Ward & Biagini, ; Guttery et al ., ), PfFNT (Wu et al ., ; Golldack et al ., ), PbENT1 (Arora et al ., ), and the Plasmodium vivax homologue of ENT1 (PvENT1) (Deniskin et al ., ). The successful expression of a foreign transporter in yeast often requires codon‐optimisation of the coding sequence and/or the modification of the protein's N‐terminus by fusion or deletion of a polypeptide segment (Reis et al ., ; Drake, Serrano & Perez‐Castineira, ; Rotmann et al ., ; Blume et al ., ).…”

Section: The Plasmodium Transportomementioning

confidence: 97%

The transportome of the malaria parasite

Martin

2019

Biological Reviews

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Membrane transport proteins, also known as transporters, control the movement of ions, nutrients, metabolites, and waste products across the membranes of a cell and are central to its biology. Proteins of this type also serve as drug targets and are key players in the phenomenon of drug resistance. The malaria parasite has a relatively reduced transportome, with only approximately 2.5% of its genes encoding transporters. Even so, assigning functions and physiological roles to these proteins, and ascertaining their contributions to drug action and drug resistance, has been very challenging. This review presents a detailed critique and synthesis of the disruption phenotypes, protein subcellular localisations, protein functions (observed or predicted), and links to antimalarial drug resistance for each of the parasite's transporter genes. The breadth and depth of the gene disruption data are particularly impressive, with at least one phenotype determined in the parasite's asexual blood stage for each transporter gene, and multiple phenotypes available for 76% of the genes. Analysis of the curated data set revealed there to be relatively little redundancy in the Plasmodium transportome; almost two‐thirds of the parasite's transporter genes are essential or required for normal growth in the asexual blood stage of the parasite, and this proportion increased to 78% when the disruption phenotypes available for the other parasite life stages were included in the analysis. These observations, together with the finding that 22% of the transportome is implicated in the parasite's resistance to existing antimalarials and/or drugs within the development pipeline, indicate that transporters are likely to serve, or are already serving, as drug targets. Integration of the different biological and bioinformatic data sets also enabled the selection of candidates for transport processes known to be essential for parasite survival, but for which the underlying proteins have thus far remained undiscovered. These include potential transporters of pantothenate, isoleucine, or isopentenyl diphosphate, as well as putative anion‐selective channels that may serve as the pore component of the parasite's ‘new permeation pathways’. Other novel insights into the parasite's biology included the identification of transporters for the potential development of antimalarial treatments, transmission‐blocking drugs, prophylactics, and genetically attenuated vaccines. The syntheses presented herein set a foundation for elucidating the functions and physiological roles of key members of the Plasmodium transportome and, ultimately, to explore and realise their potential as therapeutic targets.

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Targeting the Plasmodium vivax equilibrative nucleoside transporter 1 (PvENT1) for antimalarial drug development

Cited by 16 publications

References 52 publications

Substrate and Inhibitor Specificity of thePlasmodium bergheiEquilibrative Nucleoside Transporter Type 1

Substrate and Inhibitor Specificity of thePlasmodium bergheiEquilibrative Nucleoside Transporter Type 1

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

The transportome of the malaria parasite

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