Chemical and Genetic Validation of the Statin Drug Target to Treat the Helminth Disease, Schistosomiasis
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{"title"=>"Chemical and genetic validation of the statin drug target to treat the helminth disease, schistosomiasis", "type"=>"journal", "authors"=>[{"first_name"=>"Liliana", "last_name"=>"Rojo-Arreola", "scopus_author_id"=>"56095217600"}, {"first_name"=>"Thavy", "last_name"=>"Long", "scopus_author_id"=>"35237532800"}, {"first_name"=>"Dan", "last_name"=>"Asarnow", "scopus_author_id"=>"55251577400"}, {"first_name"=>"Brian M.", "last_name"=>"Suzuki", "scopus_author_id"=>"9840104300"}, {"first_name"=>"Rahul", "last_name"=>"Singh", "scopus_author_id"=>"55574239638"}, {"first_name"=>"Conor R.", "last_name"=>"Caffrey", "scopus_author_id"=>"7004425974"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"pui"=>"373070260", "sgr"=>"84900434707", "pmid"=>"24489942", "scopus"=>"2-s2.0-84900434707", "isbn"=>"1932-6203 (Electronic)\\n1932-6203 (Linking)", "doi"=>"10.1371/journal.pone.0087594", "issn"=>"19326203"}, "id"=>"dc88b9bd-186c-3327-b1ee-8d63385ce30c", "abstract"=>"The mevalonate pathway is essential in eukaryotes and responsible for a diversity of fundamental synthetic activities. 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the rate-limiting enzyme in the pathway and is targeted by the ubiquitous statin drugs to treat hypercholesterolemia. Independent reports have indicated the cidal effects of statins against the flatworm parasite, S. mansoni, and the possibility that SmHMGR is a useful drug target to develop new statin-based anti-schistosome therapies. For six commercially available statins, we demonstrate concentration- and time-dependent killing of immature (somule) and adult S. mansoni in vitro at sub-micromolar and micromolar concentrations, respectively. Cidal activity trends with statin lipophilicity whereby simvastatin and pravastatin are the most and least active, respectively. Worm death is preventable by excess mevalonate, the product of HMGR. Statin activity against somules was quantified both manually and automatically using a new, machine learning-based automated algorithm with congruent results. In addition, to chemical targeting, RNA interference (RNAi) of HMGR also kills somules in vitro and, again, lethality is blocked by excess mevalonate. Further, RNAi of HMGR of somules in vitro subsequently limits parasite survival in a mouse model of infection by up to 80%. Parasite death, either via statins or specific RNAi of HMGR, is associated with activation of apoptotic caspase activity. Together, our genetic and chemical data confirm that S. mansoni HMGR is an essential gene and the relevant target of statin drugs. We discuss our findings in context of a potential drug development program and the desired product profile for a new schistosomiasis drug.", "link"=>"http://www.mendeley.com/research/chemical-genetic-validation-statin-drug-target-treat-helminth-disease-schistosomiasis", "reader_count"=>58, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>8, "Student > Doctoral Student"=>4, "Researcher"=>10, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>1, "Student > Master"=>9, "Other"=>2, "Student > Bachelor"=>5, "Lecturer"=>1, "Professor"=>4}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>8, "Student > Doctoral Student"=>4, "Researcher"=>10, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>1, "Student > Master"=>9, "Other"=>2, "Student > Bachelor"=>5, "Lecturer"=>1, "Professor"=>4}, "reader_count_by_subject_area"=>{"Unspecified"=>5, "Biochemistry, Genetics and Molecular Biology"=>6, "Nursing and Health Professions"=>1, "Mathematics"=>1, "Agricultural and Biological Sciences"=>26, "Medicine and Dentistry"=>8, "Neuroscience"=>1, "Arts and Humanities"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Chemistry"=>6, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>8}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>6}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>26}, "Computer Science"=>{"Computer Science"=>1}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>6}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>5}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}, "Arts and Humanities"=>{"Arts and Humanities"=>1}}, "reader_count_by_country"=>{"Netherlands"=>1, "Uruguay"=>2, "Brazil"=>1, "United Kingdom"=>1}, "group_count"=>4}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1366653"], "description"=>"<p><i>P</i>-values were determined using Student's <i>t</i>-test.</p>", "links"=>[], "tags"=>["chemical biology", "medicinal chemistry", "Drugs and devices", "Drug research and development", "drug discovery", "Global health", "Infectious diseases", "neglected tropical diseases", "schistosomiasis", "Parasitic diseases", "Infectious disease control", "statins", "somules", "dose-response", "correlations", "automated"], "article_id"=>918206, "categories"=>["Medicine", "Chemistry"], "users"=>["Liliana Rojo-Arreola", "Thavy Long", "Dan Asarnow", "Brian M. Suzuki", "Rahul Singh", "Conor R. Caffrey"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087594.t001", "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cidal_activity_of_statins_against_somules_in_vitro_dose_response_correlations_between_the_automated_and_manual_assays_/918206", "title"=>"Cidal activity of statins against somules <i>in vitro</i>: dose-response correlations between the automated and manual assays.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-01-29 04:02:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/1366649"], "description"=>"<p><b>A</b>. Newly transformed somules were incubated in the presence of either 10 µM simvastatin (±100 µM mevalonate) or pravastatin for the times indicated. Caspase activity was then measured using the fluorescent substrate Z-DEVD-R110 as described in the text and is expressed relative to DMSO controls. Bars represent means ± S.D. across two independent experiments. Significance (p<0.05) was measured using Student's <i>t</i>-test and is indicated with an asterisk. <b>B</b>. As for A, but employing adult worms. Bars represent means ± S.D. across two independent experiments. Significance (p<0.05) was measured using Student's <i>t</i>-test and is indicated with an asterisk.</p>", "links"=>[], "tags"=>["chemical biology", "medicinal chemistry", "Drugs and devices", "Drug research and development", "drug discovery", "Global health", "Infectious diseases", "neglected tropical diseases", "schistosomiasis", "Parasitic diseases", "Infectious disease control", "apoptosis", "somules"], "article_id"=>918202, "categories"=>["Medicine", "Chemistry"], "users"=>["Liliana Rojo-Arreola", "Thavy Long", "Dan Asarnow", "Brian M. Suzuki", "Rahul Singh", "Conor R. Caffrey"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087594.g006", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Simvastatin_but_not_pravastatin_induces_apoptosis_in_somules_and_adult_worms_/918202", "title"=>"Simvastatin, but not pravastatin, induces apoptosis in somules and adult worms.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-29 04:02:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/1366644"], "description"=>"<p>Adult worms were incubated out to six days in the presence of the concentrations of statins indicated. A severity score was devised based on previously employed phenotype descriptors that record changes in movement, shape, translucence, surface integrity, and the ability of the parasite to adhere to the floor of the culture plate well <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087594#pone.0087594-Abdulla1\" target=\"_blank\">[35]</a>. Each descriptor was assigned a score of 1, except where damage to the parasite's surface was evident, in which case the maximum score of 4 was awarded. For each concentration tested, each bar (from left to right) represents simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin and pravastatin. At the bottom, co-incubation with mevalonate (2 mM) for three days prior to the addition of 20 µM simvastatin or lovastatin prevented worm degeneration. Representative data from two independent experiments are shown.</p>", "links"=>[], "tags"=>["chemical biology", "medicinal chemistry", "Drugs and devices", "Drug research and development", "drug discovery", "Global health", "Infectious diseases", "neglected tropical diseases", "schistosomiasis", "Parasitic diseases", "Infectious disease control", "concentration-dependent", "statin", "drugs", "mansoni"], "article_id"=>918197, "categories"=>["Medicine", "Chemistry"], "users"=>["Liliana Rojo-Arreola", "Thavy Long", "Dan Asarnow", "Brian M. Suzuki", "Rahul Singh", "Conor R. Caffrey"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087594.g002", "stats"=>{"downloads"=>0, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Time_and_concentration_dependent_effects_of_six_statin_drugs_on_adult_S_mansoni_in_vitro_/918197", "title"=>"Time- and concentration-dependent effects of six statin drugs on adult <i>S. mansoni in vitro</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-29 04:02:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/1366643"], "description"=>"<p>Newly transformed somules were incubated out to four days in the presence of the concentrations of statins indicated. The percentage of degenerate worms was measured both manually (dashed curves) and using a new automated algorithm (solid curves) as described in the text. Points represent means ± S.D. across two independent experiments each in duplicate. ED<sub>50</sub> values are inserted above the curves. Mevalonate (100 µM) prevented worm-kill by 1 µM simvastatin and is indicated by the single square point. Image panels display somules cultured for four days; (A) DMSO control, (B) 1 µM simvastatin (indicating the rounded and darkened (degenerate) response) and (C) 1 µM simvastatin plus 100 µM mevalonate. Bar in Panel A = 100 µm.</p>", "links"=>[], "tags"=>["chemical biology", "medicinal chemistry", "Drugs and devices", "Drug research and development", "drug discovery", "Global health", "Infectious diseases", "neglected tropical diseases", "schistosomiasis", "Parasitic diseases", "Infectious disease control", "somules", "statins", "manually", "learning-based", "automated"], "article_id"=>918196, "categories"=>["Medicine", "Chemistry"], "users"=>["Liliana Rojo-Arreola", "Thavy Long", "Dan Asarnow", "Brian M. Suzuki", "Rahul Singh", "Conor R. Caffrey"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087594.g001", "stats"=>{"downloads"=>0, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Concentration_dependent_killing_of_S_mansoni_somules_by_six_commercial_statins_as_measured_manually_and_using_a_machine_learning_based_automated_algorithm_/918196", "title"=>"Concentration-dependent killing of <i>S. mansoni</i> somules by six commercial statins as measured manually and using a machine learning-based automated algorithm.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-29 04:02:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/1366652"], "description"=>"<p>The enzymes are numbered in bold typeface and their respective products are boxed; synthetic inhibitors are indicated in red. GenBank entries for each enzyme are: <b>1</b>- CCD58635; <b>2</b>- CAZ30720; <b>3</b>- CCD79354; <b>4</b>- CCD76423; <b>5</b>- CCD60126; <b>6</b>- CCD78373; <b>7</b>- CCD81269; <b>8</b>- α-subunit- XP_002580188; β-subunit- CCD82339; <b>9</b>- α-subunit- CCD77887; β-subunit- CCD79051. FTI  =  farnesyl transferase inhibitor; GGTI  =  geranylgeranyl transferase inhibitor.</p>", "links"=>[], "tags"=>["chemical biology", "medicinal chemistry", "Drugs and devices", "Drug research and development", "drug discovery", "Global health", "Infectious diseases", "neglected tropical diseases", "schistosomiasis", "Parasitic diseases", "Infectious disease control", "mevalonate", "pathway"], "article_id"=>918205, "categories"=>["Medicine", "Chemistry"], "users"=>["Liliana Rojo-Arreola", "Thavy Long", "Dan Asarnow", "Brian M. Suzuki", "Rahul Singh", "Conor R. Caffrey"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087594.g008", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Overview_of_the_mevalonate_pathway_in_S_mansoni_/918205", "title"=>"Overview of the mevalonate pathway in <i>S. mansoni</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-29 04:02:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/1366651"], "description"=>"<p>Somules were incubated with dsRNA to HMGR (±500 µM mevalonate) or mCherry for 25 days. Caspase activity was then measured using the fluorescent substrate Z-DEVD-R110 as described in the text. Data are expressed as the fold increase in caspase activity relative to somules exposed to mCherry dsRNA. Bars represent means ± S.D. across two independent experiments. Significance (p<0.05) was measured using Student's <i>t</i>-test and is indicated with an asterisk.</p>", "links"=>[], "tags"=>["chemical biology", "medicinal chemistry", "Drugs and devices", "Drug research and development", "drug discovery", "Global health", "Infectious diseases", "neglected tropical diseases", "schistosomiasis", "Parasitic diseases", "Infectious disease control", "smhmgr", "apoptosis", "preventable", "excess"], "article_id"=>918204, "categories"=>["Medicine", "Chemistry"], "users"=>["Liliana Rojo-Arreola", "Thavy Long", "Dan Asarnow", "Brian M. Suzuki", "Rahul Singh", "Conor R. Caffrey"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087594.g007", "stats"=>{"downloads"=>0, "page_views"=>34, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_RNAi_of_SmHMGR_induces_apoptosis_in_somules_which_is_preventable_by_excess_mevalonate_/918204", "title"=>"RNAi of SmHMGR induces apoptosis in somules, which is preventable by excess mevalonate.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-29 04:02:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/1366648"], "description"=>"<p>Newly transformed somules were incubated for 2.5 days in the presence of mCherry dsRNA or HMGR dsRNA as described in the text. Parasites were then injected subcutaneously into Swiss Webster mice (5 mice per dsRNA treatment). After 34 days, mice were euthanized and the portal system perfused to recover parasites for counting. Bars represent means ± S.D. across two independent experiments. Using Student's <i>t</i>-test, worm recovery after exposure to HMGR-dsRNA was significantly different from mCherry controls (<i>p</i><0.01).</p>", "links"=>[], "tags"=>["chemical biology", "medicinal chemistry", "Drugs and devices", "Drug research and development", "drug discovery", "Global health", "Infectious diseases", "neglected tropical diseases", "schistosomiasis", "Parasitic diseases", "Infectious disease control", "smhmgr", "compromises", "parasite"], "article_id"=>918201, "categories"=>["Medicine", "Chemistry"], "users"=>["Liliana Rojo-Arreola", "Thavy Long", "Dan Asarnow", "Brian M. Suzuki", "Rahul Singh", "Conor R. Caffrey"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087594.g005", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_RNAi_of_SmHMGR_severely_compromises_parasite_survival_in_vivo_/918201", "title"=>"RNAi of SmHMGR severely compromises parasite survival <i>in vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-29 04:02:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/1366645"], "description"=>"<p>Newly transformed somules were incubated with HMGR- or mCherry-dsRNA for seven days as described in the text. RNAi was measured by qRT-PCR and data expressed relative to data for mCherry dsRNA controls. To assess for potential off-targeting by HMGR-dsRNA, the expression of a <i>S. mansoni</i> cysteine protease inhibitor, cystatin (Cys: AY334553.1), and the gut-associated cysteine protease, cathepsin B1.1 (AJ506157), was also measured. Bars represent means ± S.D. across two independent experiments each in duplicate. Using Student's <i>t</i>-test, gene suppression in the HMGR-dsRNA treated sample is significantly different from the mCherry controls (<i>p</i><0.01).</p>", "links"=>[], "tags"=>["chemical biology", "medicinal chemistry", "Drugs and devices", "Drug research and development", "drug discovery", "Global health", "Infectious diseases", "neglected tropical diseases", "schistosomiasis", "Parasitic diseases", "Infectious disease control", "smhmgr", "selective"], "article_id"=>918199, "categories"=>["Medicine", "Chemistry"], "users"=>["Liliana Rojo-Arreola", "Thavy Long", "Dan Asarnow", "Brian M. Suzuki", "Rahul Singh", "Conor R. Caffrey"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087594.g003", "stats"=>{"downloads"=>0, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_RNAi_of_SmHMGR_is_selective_for_the_target_/918199", "title"=>"RNAi of SmHMGR is selective for the target.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-29 04:02:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/1366647"], "description"=>"<p>Newly transformed somules were incubated for the times indicated in the presence of mCherry-dsRNA (control) or HMGR-dsRNA with and without the presence of 500 µM mevalonate, as described in the text. Bars represent means ± S.D. across two independent experiments each in duplicate. The number of degenerate worms in the HMGR-dsRNA-treated samples taken on Day 25 is significantly different from both the mCherry controls and HMG-dsRNA-treated samples that had also been incubated in the presence of mevalonate (Student's <i>t</i>-test; <i>p</i><0.01). Image panels display somules on Day 25 incubated with (A) mCherry-dsRNA (control), (B) HMG-dsRNA and (C) HMG-dsRNA plus 500 µM mevalonate. Arrowheads highlight a dead (left) and degenerate worm (right). Bar in panel A = 100 µm.</p>", "links"=>[], "tags"=>["chemical biology", "medicinal chemistry", "Drugs and devices", "Drug research and development", "drug discovery", "Global health", "Infectious diseases", "neglected tropical diseases", "schistosomiasis", "Parasitic diseases", "Infectious disease control", "smhmgr", "kills", "somules", "preventable", "excess"], "article_id"=>918200, "categories"=>["Medicine", "Chemistry"], "users"=>["Liliana Rojo-Arreola", "Thavy Long", "Dan Asarnow", "Brian M. Suzuki", "Rahul Singh", "Conor R. Caffrey"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0087594.g004", "stats"=>{"downloads"=>0, "page_views"=>32, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_RNAi_of_SmHMGR_kills_somules_and_killing_is_preventable_by_excess_mevalonate_/918200", "title"=>"RNAi of SmHMGR kills somules and killing is preventable by excess mevalonate.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-01-29 04:02:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/1366654", "https://ndownloader.figshare.com/files/1366655", "https://ndownloader.figshare.com/files/1366656", "https://ndownloader.figshare.com/files/1366657"], "description"=>"<div><p>The mevalonate pathway is essential in eukaryotes and responsible for a diversity of fundamental synthetic activities. 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the rate-limiting enzyme in the pathway and is targeted by the ubiquitous statin drugs to treat hypercholesterolemia. Independent reports have indicated the cidal effects of statins against the flatworm parasite, <i>S. mansoni</i>, and the possibility that SmHMGR is a useful drug target to develop new statin-based anti-schistosome therapies. For six commercially available statins, we demonstrate concentration- and time-dependent killing of immature (somule) and adult <i>S. mansoni in vitro</i> at sub-micromolar and micromolar concentrations, respectively. Cidal activity trends with statin lipophilicity whereby simvastatin and pravastatin are the most and least active, respectively. Worm death is preventable by excess mevalonate, the product of HMGR. Statin activity against somules was quantified both manually and automatically using a new, machine learning-based automated algorithm with congruent results. In addition, to chemical targeting, RNA interference (RNAi) of HMGR also kills somules <i>in vitro</i> and, again, lethality is blocked by excess mevalonate. Further, RNAi of HMGR of somules <i>in vitro</i> subsequently limits parasite survival in a mouse model of infection by up to 80%. Parasite death, either via statins or specific RNAi of HMGR, is associated with activation of apoptotic caspase activity. Together, our genetic and chemical data confirm that <i>S. mansoni</i> HMGR is an essential gene and the relevant target of statin drugs. We discuss our findings in context of a potential drug development program and the desired product profile for a new schistosomiasis drug.</p></div>", "links"=>[], "tags"=>["chemical biology", "medicinal chemistry", "Drugs and devices", "Drug research and development", "drug discovery", "Global health", "Infectious diseases", "neglected tropical diseases", "schistosomiasis", "Parasitic diseases", "Infectious disease control", "validation", "statin", "helminth"], "article_id"=>918207, "categories"=>["Medicine", "Chemistry"], "users"=>["Liliana Rojo-Arreola", "Thavy Long", "Dan Asarnow", "Brian M. Suzuki", "Rahul Singh", "Conor R. Caffrey"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0087594.s001", "https://dx.doi.org/10.1371/journal.pone.0087594.s002", "https://dx.doi.org/10.1371/journal.pone.0087594.s003", "https://dx.doi.org/10.1371/journal.pone.0087594.s004"], "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Chemical_and_Genetic_Validation_of_the_Statin_Drug_Target_to_Treat_the_Helminth_Disease_Schistosomiasis_/918207", "title"=>"Chemical and Genetic Validation of the Statin Drug Target to Treat the Helminth Disease, Schistosomiasis", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-01-29 04:02:32"}

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