Plasmodium falciparum Parasites Are Killed by a Transition State Analogue of Purine Nucleoside Phosphorylase in a Primate Animal Model
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{"title"=>"Plasmodium falciparum parasites are killed by a transition state analogue of purine nucleoside phosphorylase in a primate animal model", "type"=>"journal", "authors"=>[{"first_name"=>"María B.", "last_name"=>"Cassera", "scopus_author_id"=>"6506414660"}, {"first_name"=>"Keith Z.", "last_name"=>"Hazleton", "scopus_author_id"=>"16070169300"}, {"first_name"=>"Emilio F.", "last_name"=>"Merino", "scopus_author_id"=>"8148009100"}, {"first_name"=>"Nicanor", "last_name"=>"Obaldia", "scopus_author_id"=>"6602369580"}, {"first_name"=>"Meng Chiao", "last_name"=>"Ho", "scopus_author_id"=>"26040801900"}, {"first_name"=>"Andrew S.", "last_name"=>"Murkin", "scopus_author_id"=>"14008047500"}, {"first_name"=>"Richard", "last_name"=>"DePinto", "scopus_author_id"=>"55177910300"}, {"first_name"=>"Jemy A.", "last_name"=>"Gutierrez", "scopus_author_id"=>"8588195200"}, {"first_name"=>"Steven C.", "last_name"=>"Almo", "scopus_author_id"=>"7006885362"}, {"first_name"=>"Gary B.", "last_name"=>"Evans", "scopus_author_id"=>"57192544761"}, {"first_name"=>"Yarlagadda S.", "last_name"=>"Babu", "scopus_author_id"=>"35466888400"}, {"first_name"=>"Vern L.", "last_name"=>"Schramm", "scopus_author_id"=>"35509217100"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"362904732", "issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "doi"=>"10.1371/journal.pone.0026916", "scopus"=>"2-s2.0-80855133585", "pmid"=>"22096507", "sgr"=>"80855133585"}, "id"=>"5d36b442-192e-37fc-982e-38982b2554d5", "abstract"=>"Plasmodium falciparum causes most of the one million annual deaths from malaria. Drug resistance is widespread and novel agents against new targets are needed to support combination-therapy approaches promoted by the World Health Organization. Plasmodium species are purine auxotrophs. Blocking purine nucleoside phosphorylase (PNP) kills cultured parasites by purine starvation. DADMe-Immucillin-G (BCX4945) is a transition state analogue of human and Plasmodium PNPs, binding with picomolar affinity. Here, we test BCX4945 in Aotus primates, an animal model for Plasmodium falciparum infections. Oral administration of BCX4945 for seven days results in parasite clearance and recrudescence in otherwise lethal infections of P. falciparum in Aotus monkeys. The molecular action of BCX4945 is demonstrated in crystal structures of human and P. falciparum PNPs. Metabolite analysis demonstrates that PNP blockade inhibits purine salvage and polyamine synthesis in the parasites. The efficacy, oral availability, chemical stability, unique mechanism of action and low toxicity of BCX4945 demonstrate potential for combination therapies with this novel antimalarial agent.", "link"=>"http://www.mendeley.com/research/plasmodium-falciparum-parasites-killed-transition-state-analogue-purine-nucleoside-phosphorylase-pri", "reader_count"=>48, "reader_count_by_academic_status"=>{"Unspecified"=>3, "Professor > Associate Professor"=>2, "Researcher"=>11, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>13, "Student > Postgraduate"=>3, "Student > Master"=>7, "Other"=>3, "Student > Bachelor"=>2, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>3, "Professor > Associate Professor"=>2, "Researcher"=>11, "Student > Doctoral Student"=>2, "Student > Ph. D. Student"=>13, "Student > Postgraduate"=>3, "Student > Master"=>7, "Other"=>3, "Student > Bachelor"=>2, "Lecturer"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>4, "Biochemistry, Genetics and Molecular Biology"=>5, "Nursing and Health Professions"=>1, "Agricultural and Biological Sciences"=>24, "Medicine and Dentistry"=>6, "Chemistry"=>6, "Psychology"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Chemistry"=>{"Chemistry"=>6}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>24}, "Computer Science"=>{"Computer Science"=>1}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>4}}, "reader_count_by_country"=>{"United States"=>1, "Norway"=>1, "Brazil"=>1, "United Kingdom"=>2, "India"=>1}, "group_count"=>5}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/363335", "https://ndownloader.figshare.com/files/363361", "https://ndownloader.figshare.com/files/363400", "https://ndownloader.figshare.com/files/363457", "https://ndownloader.figshare.com/files/363519", "https://ndownloader.figshare.com/files/363594", "https://ndownloader.figshare.com/files/363661", "https://ndownloader.figshare.com/files/363709", "https://ndownloader.figshare.com/files/363728", "https://ndownloader.figshare.com/files/363757", "https://ndownloader.figshare.com/files/363786"], "description"=>"<div><p><em>Plasmodium falciparum</em> causes most of the one million annual deaths from malaria. Drug resistance is widespread and novel agents against new targets are needed to support combination-therapy approaches promoted by the World Health Organization. <em>Plasmodium</em> species are purine auxotrophs. Blocking purine nucleoside phosphorylase (PNP) kills cultured parasites by purine starvation. DADMe-Immucillin-G (BCX4945) is a transition state analogue of human and <em>Plasmodium</em> PNPs, binding with picomolar affinity. Here, we test BCX4945 in <em>Aotus</em> primates, an animal model for <em>Plasmodium falciparum</em> infections. Oral administration of BCX4945 for seven days results in parasite clearance and recrudescence in otherwise lethal infections of <em>P. falciparum</em> in <em>Aotus</em> monkeys. The molecular action of BCX4945 is demonstrated in crystal structures of human and <em>P. falciparum</em> PNPs. Metabolite analysis demonstrates that PNP blockade inhibits purine salvage and polyamine synthesis in the parasites. The efficacy, oral availability, chemical stability, unique mechanism of action and low toxicity of BCX4945 demonstrate potential for combination therapies with this novel antimalarial agent.</p> </div>", "links"=>[], "tags"=>["parasites", "are", "killed", "analogue", "purine", "nucleoside", "phosphorylase", "primate"], "article_id"=>131808, "categories"=>["Cancer", "Biochemistry", "Chemistry", "Microbiology"], "users"=>["María B. Cassera", "Keith Z. Hazleton", "Emilio F. Merino", "Nicanor Obaldia III", "Meng-Chiao Ho", "Andrew S. Murkin", "Richard DePinto", "Jemy A. Gutierrez", "Steven C. Almo", "Gary B. Evans", "Yarlagadda S. Babu", "Vern L. Schramm"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0026916.s001", "https://dx.doi.org/10.1371/journal.pone.0026916.s002", "https://dx.doi.org/10.1371/journal.pone.0026916.s003", "https://dx.doi.org/10.1371/journal.pone.0026916.s004", "https://dx.doi.org/10.1371/journal.pone.0026916.s005", "https://dx.doi.org/10.1371/journal.pone.0026916.s006", "https://dx.doi.org/10.1371/journal.pone.0026916.s007", "https://dx.doi.org/10.1371/journal.pone.0026916.s008", "https://dx.doi.org/10.1371/journal.pone.0026916.s009", "https://dx.doi.org/10.1371/journal.pone.0026916.s010", "https://dx.doi.org/10.1371/journal.pone.0026916.s011"], "stats"=>{"downloads"=>17, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Plasmodium_falciparum_Parasites_Are_Killed_by_a_Transition_State_Analogue_of_Purine_Nucleoside_Phosphorylase_in_a_Primate_Animal_Model/131808", "title"=>"<em>Plasmodium falciparum</em> Parasites Are Killed by a Transition State Analogue of Purine Nucleoside Phosphorylase in a Primate Animal Model", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-11-11 00:30:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/713541"], "description"=>"<p>Data are mean ± s.d. from two experiments, <i>p</i> values are in parentheses.</p>", "links"=>[], "tags"=>["purine", "levels", "cultured", "infected-erythrocytes", "erythrocytes", "24"], "article_id"=>383885, "categories"=>["Microbiology", "Biochemistry", "Chemistry", "Infectious Diseases"], "users"=>["María B. Cassera", "Keith Z. Hazleton", "Emilio F. Merino", "Nicanor Obaldia III", "Meng-Chiao Ho", "Andrew S. Murkin", "Richard DePinto", "Jemy A. Gutierrez", "Steven C. Almo", "Gary B. Evans", "Yarlagadda S. Babu", "Vern L. Schramm"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026916.t001", "stats"=>{"downloads"=>4, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Polyamine_and_purine_levels_in_cultured_P_falciparum_infected_erythrocytes_and_human_erythrocytes_after_24_h_treatment_with_5_M_BCX4945_/383885", "title"=>"Polyamine and purine levels in cultured <i>P. falciparum</i> infected-erythrocytes and human erythrocytes after 24 h treatment with 5 µM BCX4945.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-11-11 01:04:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/713621"], "description"=>"<p>*Samples were collected before monkeys were infected with <i>P. falciparum</i> and four days after infection started.</p>", "links"=>[], "tags"=>["inosine", "levels", "plasma", "cells"], "article_id"=>383971, "categories"=>["Microbiology", "Biochemistry", "Chemistry", "Infectious Diseases"], "users"=>["María B. Cassera", "Keith Z. Hazleton", "Emilio F. Merino", "Nicanor Obaldia III", "Meng-Chiao Ho", "Andrew S. Murkin", "Richard DePinto", "Jemy A. Gutierrez", "Steven C. Almo", "Gary B. Evans", "Yarlagadda S. Babu", "Vern L. Schramm"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026916.t003", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hypoxanthine_and_inosine_levels_in_Aotus_monkeys_plasma_and_blood_cells_before_and_during_P_falciparum_infection_/383971", "title"=>"Hypoxanthine and inosine levels in <i>Aotus</i> monkeys' plasma and blood cells before and during <i>P. falciparum</i> infection<sup>*</sup>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-11-11 01:06:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/713252"], "description"=>"<p>(<b>A</b>) Parasitaemia in infected untreated monkey (IUM, <i>n</i> = 1) or infected treated monkeys (ITM, <i>n</i> = 3). The arrow indicates mefloquine treatment to cure the infected untreated control monkey. Grey bar on the x-axis indicates days of treatment. (<b>B</b>) Blood cell PNP activity was assayed from untreated (<i>n</i> = 1) and treated monkeys (<i>n</i> = 3, means ± s.d.). Each sample was analyzed in triplicate. (<b>C</b>) Samples from blood cells and plasma were analyzed by UPLC-MS/MS. The (−4) time point indicates blood was taken before the monkey was infected. The (0) time point indicates that blood was drawn before the treatment started. Day 1 reflects parasitaemia or metabolite levels 24 h after the first dose and the metabolic effect of two BCX4945 doses within 24 h (also for days 2 to 5). Days 12 and 18 are counted from the start of treatment.</p>", "links"=>[], "tags"=>["bcx4945", "inhibits", "pnp", "clears", "infected"], "article_id"=>383598, "categories"=>["Microbiology", "Biochemistry", "Chemistry", "Infectious Diseases"], "users"=>["María B. Cassera", "Keith Z. Hazleton", "Emilio F. Merino", "Nicanor Obaldia III", "Meng-Chiao Ho", "Andrew S. Murkin", "Richard DePinto", "Jemy A. Gutierrez", "Steven C. Almo", "Gary B. Evans", "Yarlagadda S. Babu", "Vern L. Schramm"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026916.g003", "stats"=>{"downloads"=>2, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Oral_administration_of_BCX4945_inhibits_PNP_and_clears_P_falciparum_from_infected_Aotus_monkeys_/383598", "title"=>"Oral administration of BCX4945 inhibits PNP and clears <i>P. falciparum</i> from infected <i>Aotus</i> monkeys.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-11-11 00:59:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/713391"], "description"=>"<p>Crystal structures of hPNP-BCX4945-PO<sub>4</sub> (<b>A</b>) and <i>Pf</i>PNP-BCX4945-PO<sub>4</sub> (<b>B</b>) were determined to 2.3 and 2.0 Å resolution, respectively. BCX4945 (grey) active site residues (yellow), residues from adjacent subunits (green) and phosphate (orange) are indicated. Hydrogen bonds are indicated as black dashed lines. The ion-pair interaction between the ribocation mimic and phosphate is indicated as a magenta dashed line with the distances indicated.</p>", "links"=>[], "tags"=>["bcx4945", "phosphate", "bound", "hpnp"], "article_id"=>383737, "categories"=>["Microbiology", "Biochemistry", "Chemistry", "Infectious Diseases"], "users"=>["María B. Cassera", "Keith Z. Hazleton", "Emilio F. Merino", "Nicanor Obaldia III", "Meng-Chiao Ho", "Andrew S. Murkin", "Richard DePinto", "Jemy A. Gutierrez", "Steven C. Almo", "Gary B. Evans", "Yarlagadda S. Babu", "Vern L. Schramm"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026916.g004", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Stereo_view_crystal_structure_of_BCX4945_and_phosphate_bound_to_hPNP_and_Pf_PNP_/383737", "title"=>"Stereo view crystal structure of BCX4945 and phosphate bound to hPNP and <i>Pf</i>PNP.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-11-11 01:02:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/713149"], "description"=>"<p>(<b>A</b>) Chemical structure and effect of BCX4945 on <i>in vitro</i> growth of different <i>P. falciparum</i> strains. Parasites were incubated in the presence of the indicated concentrations of BCX4945 for 72 h at 1% hematocrit, followed by DNA quantitation. IC<sub>50</sub> values were calculated from fits (Origin software) to the overall response curve. The graph is constructed by individual point connections. (<b>B, C</b>) Counts per minute (cpm) levels of [<sup>3</sup>H]inosine and [<sup>3</sup>H]hypoxanthine metabolically incorporated into purine derivatives. <i>P. falciparum</i> infected-red blood cells in schizont and trophozoite stages were metabolically labeled with [<sup>3</sup>H]inosine or [<sup>3</sup>H]hypoxanthine in the absence or presence of 10 µM of BCX4945. Labeled inosine (INO-S) and hypoxanthine (HX-S) present in the supernatant. Means ± s.d. from triplicates are represented.</p>", "links"=>[], "tags"=>["inhibits", "pnp", "inosine"], "article_id"=>383498, "categories"=>["Microbiology", "Biochemistry", "Chemistry", "Infectious Diseases"], "users"=>["María B. Cassera", "Keith Z. Hazleton", "Emilio F. Merino", "Nicanor Obaldia III", "Meng-Chiao Ho", "Andrew S. Murkin", "Richard DePinto", "Jemy A. Gutierrez", "Steven C. Almo", "Gary B. Evans", "Yarlagadda S. Babu", "Vern L. Schramm"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026916.g002", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_BCX4945_inhibits_PNP_to_block_inosine_salvage_/383498", "title"=>"BCX4945 inhibits PNP to block inosine salvage.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-11-11 00:58:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/713583"], "description"=>"<p>Parasites per µl×10<sup>3</sup>.</p><p>*One dose of mefloquine (40 mg kg<sup>−1</sup>);</p>†<p>one dose of artesunic acid (33 mg kg<sup>−1</sup>). (IUM), Infected untreated monkey. (ITM), Infected treated monkey.</p>", "links"=>[], "tags"=>["monkeys", "orally", "treated", "50", "mg", "bcx4945"], "article_id"=>383927, "categories"=>["Microbiology", "Biochemistry", "Chemistry", "Infectious Diseases"], "users"=>["María B. Cassera", "Keith Z. Hazleton", "Emilio F. Merino", "Nicanor Obaldia III", "Meng-Chiao Ho", "Andrew S. Murkin", "Richard DePinto", "Jemy A. Gutierrez", "Steven C. Almo", "Gary B. Evans", "Yarlagadda S. Babu", "Vern L. Schramm"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026916.t002", "stats"=>{"downloads"=>1, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Parasitaemia_values_of_infected_Aotus_monkeys_orally_treated_with_50_mg_kg_8722_1_of_BCX4945_twice_a_day_for_7_days_/383927", "title"=>"Parasitaemia values of infected-<i>Aotus</i> monkeys orally treated with 50 mg kg<sup>−1</sup> of BCX4945 twice a day for 7 days.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-11-11 01:05:27"}
  • {"files"=>["https://ndownloader.figshare.com/files/712977"], "description"=>"<p><b>Purine pathway: AMP</b>, adenosine 5′-monophosphate; <b>ADP</b>, adenosine 5′-diphosphate; <b>ATP</b>, adenosine 5′-triphosphate; <b>IMP</b>, inosine 5′-monophosphate; <b>XMP</b>, xanthosine 5′-monophosphate; <b>GMP</b>, guanosine 5′-monophosphate; <b>MTA</b>, methylthioadenosine; <b>MTI</b>, methylthioinosine; <b>AdS</b>, adenylosuccinate; <b>hADA</b>, human adenosine deaminase; <b>hPNP</b>, human purine nucleoside phosphorylase; <b>hHGPRT</b>, human hypoxanthine-guanine phosphoribosyl transferase; <b>hAK</b>, human adenosine kinase; <b>hAMPDA</b>, human adenosine 5′-monophosphate deaminase; <b>hAPRT</b>, human adenine phosphoribosyl transferase; <b><i>Pf</i></b><b>ADA</b>, <i>P. falciparum</i> adenosine deaminase; <b><i>Pf</i></b><b>PNP</b>, <i>P. falciparum</i> purine nucleoside phosphorylase; <b><i>Pf</i></b><b>HGXPRT</b>, <i>P. falciparum</i> hypoxanthine-guanine-xanthine phosphoribosyl transferase; <b><i>Pf</i></b><b>AMPDA</b>, <i>P. falciparum</i> adenosine 5′-monophosphate deaminase; <b><i>Pf</i></b><b>IMPDH</b>, <i>P. falciparum</i> inosine 5′-monophosphate dehydrogenase; <b><i>Pf</i></b><b>GMPs</b>, <i>P. falciparum</i> guanosine 5′-monophosphate synthase; <b><i>Pf</i></b><b>AdSS</b>, adenylosuccinate synthase; <b><i>Pf</i></b><b>AdSL</b>, adenylosuccinate lyase. <b>Polyamine pathway: AdoMet</b>, <i>S</i>-adenosylmethionine; <b>AdoHC</b>, <i>S</i>-adenosylhomocysteine; <b>HC</b>, homocysteine; <b>Met</b>, methionine; <b>dcAdoMet</b>, decarboxylated <i>S</i>-adenosylmethionine; <b><i>Pf</i></b><b>SpdSyn</b>, <i>P. falciparum</i> spermidine synthase; <b><i>Pf</i></b><b>ODCAdoMetDC</b>, <i>P. falciparum</i> ornithine decarboxylase<i>/S-</i>adenosylmethionine decarboxylase; <b><i>Pf</i></b><b>MetTfase</b>, <i>P. falciparum</i> methyltransferase(s); <b><i>Pf</i></b><b>AHC</b>, <i>P. falciparum S</i>-adenosyl homocysteinase; <b><i>Pf</i></b><b>MetSyn</b>, <i>P. falciparum</i> methionine synthase; <b><i>Pf</i></b><b>AdoMetSyn</b>, <i>P. falciparum S</i>-adenosylmethionine synthase. The metabolically favored direction is indicated with bold arrows on reversible steps. The metabolic step inhibited by BCX4945 is indicated in red. Nucleoside/nucleobase transporters are indicated on each membrane: human erythrocyte nucleoside transporter (brown), <i>P. falciparum</i> NT1 transporter (blue) and yet-to-be characterized adenosine 5′-monophosphate transporter (purple).</p>", "links"=>[], "tags"=>["polyamine", "metabolisms"], "article_id"=>383327, "categories"=>["Microbiology", "Biochemistry", "Chemistry", "Infectious Diseases"], "users"=>["María B. Cassera", "Keith Z. Hazleton", "Emilio F. Merino", "Nicanor Obaldia III", "Meng-Chiao Ho", "Andrew S. Murkin", "Richard DePinto", "Jemy A. Gutierrez", "Steven C. Almo", "Gary B. Evans", "Yarlagadda S. Babu", "Vern L. Schramm"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0026916.g001", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Purine_and_polyamine_metabolisms_in_P_falciparum_infected_human_erythrocytes_/383327", "title"=>"Purine and polyamine metabolisms in <i>P. falciparum</i>-infected human erythrocytes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-11-11 00:55:27"}

PMC Usage Stats | Further Information

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