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Research ArticleArticle

Substrate and Inhibitor Specificity of the Plasmodium berghei Equilibrative Nucleoside Transporter Type 1

Avish Arora, Roman Deniskin, Yvett Sosa, Sita Nirupama Nishtala, Philipp P. Henrich, T.R. Santha Kumar, David A. Fidock and Myles H. Akabas
Molecular Pharmacology June 2016, 89 (6) 678-685; DOI: https://doi.org/10.1124/mol.115.101386
Avish Arora
Departments of Physiology and Biophysics (A.A., R.D., Y.S., S.N.N., M.H.A.) and Neuroscience and Medicine (M.H.A.), Albert Einstein College of Medicine, Bronx, New York; and Departments Microbiology and Immunology (P.P.H., T.R.S.K., D.A.F.) and Medicine (D.A.F.), Columbia University Medical Center, New York, New York
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Roman Deniskin
Departments of Physiology and Biophysics (A.A., R.D., Y.S., S.N.N., M.H.A.) and Neuroscience and Medicine (M.H.A.), Albert Einstein College of Medicine, Bronx, New York; and Departments Microbiology and Immunology (P.P.H., T.R.S.K., D.A.F.) and Medicine (D.A.F.), Columbia University Medical Center, New York, New York
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Yvett Sosa
Departments of Physiology and Biophysics (A.A., R.D., Y.S., S.N.N., M.H.A.) and Neuroscience and Medicine (M.H.A.), Albert Einstein College of Medicine, Bronx, New York; and Departments Microbiology and Immunology (P.P.H., T.R.S.K., D.A.F.) and Medicine (D.A.F.), Columbia University Medical Center, New York, New York
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Sita Nirupama Nishtala
Departments of Physiology and Biophysics (A.A., R.D., Y.S., S.N.N., M.H.A.) and Neuroscience and Medicine (M.H.A.), Albert Einstein College of Medicine, Bronx, New York; and Departments Microbiology and Immunology (P.P.H., T.R.S.K., D.A.F.) and Medicine (D.A.F.), Columbia University Medical Center, New York, New York
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Philipp P. Henrich
Departments of Physiology and Biophysics (A.A., R.D., Y.S., S.N.N., M.H.A.) and Neuroscience and Medicine (M.H.A.), Albert Einstein College of Medicine, Bronx, New York; and Departments Microbiology and Immunology (P.P.H., T.R.S.K., D.A.F.) and Medicine (D.A.F.), Columbia University Medical Center, New York, New York
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T.R. Santha Kumar
Departments of Physiology and Biophysics (A.A., R.D., Y.S., S.N.N., M.H.A.) and Neuroscience and Medicine (M.H.A.), Albert Einstein College of Medicine, Bronx, New York; and Departments Microbiology and Immunology (P.P.H., T.R.S.K., D.A.F.) and Medicine (D.A.F.), Columbia University Medical Center, New York, New York
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David A. Fidock
Departments of Physiology and Biophysics (A.A., R.D., Y.S., S.N.N., M.H.A.) and Neuroscience and Medicine (M.H.A.), Albert Einstein College of Medicine, Bronx, New York; and Departments Microbiology and Immunology (P.P.H., T.R.S.K., D.A.F.) and Medicine (D.A.F.), Columbia University Medical Center, New York, New York
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Myles H. Akabas
Departments of Physiology and Biophysics (A.A., R.D., Y.S., S.N.N., M.H.A.) and Neuroscience and Medicine (M.H.A.), Albert Einstein College of Medicine, Bronx, New York; and Departments Microbiology and Immunology (P.P.H., T.R.S.K., D.A.F.) and Medicine (D.A.F.), Columbia University Medical Center, New York, New York
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Abstract

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 (IC50 = 3.7 µM) and guanosine (IC50 = 21.3 µM) 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.

Footnotes

    • Received August 14, 2015.
    • Accepted April 4, 2016.
  • This research was supported by the Albert Einstein College of Medicine, the National Institutes of Health National Institute of Allergy and Infectious Diseases [Grant R01AI116665 (to M.H.A.)], and in part by the National Institutes of Health National Institute of General Medical Sciences [Medical Scientist Training Program Grant T32GM007288 (A.A. and R.D.)].

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • dx.doi.org/10.1124/mol.115.101386.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 89 (6)
Molecular Pharmacology
Vol. 89, Issue 6
1 Jun 2016
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Research ArticleArticle

Inhibitors of the Murine Malaria Purine Transporter PbENT1

Avish Arora, Roman Deniskin, Yvett Sosa, Sita Nirupama Nishtala, Philipp P. Henrich, T.R. Santha Kumar, David A. Fidock and Myles H. Akabas
Molecular Pharmacology June 1, 2016, 89 (6) 678-685; DOI: https://doi.org/10.1124/mol.115.101386

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Research ArticleArticle

Inhibitors of the Murine Malaria Purine Transporter PbENT1

Avish Arora, Roman Deniskin, Yvett Sosa, Sita Nirupama Nishtala, Philipp P. Henrich, T.R. Santha Kumar, David A. Fidock and Myles H. Akabas
Molecular Pharmacology June 1, 2016, 89 (6) 678-685; DOI: https://doi.org/10.1124/mol.115.101386
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