Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral Effects
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{"title"=>"Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral Effects", "type"=>"journal", "authors"=>[{"first_name"=>"Andreas", "last_name"=>"Jurgeit", "scopus_author_id"=>"22957849800"}, {"first_name"=>"Robert", "last_name"=>"McDowell", "scopus_author_id"=>"56370383500"}, {"first_name"=>"Stefan", "last_name"=>"Moese", "scopus_author_id"=>"57189017536"}, {"first_name"=>"Eric", "last_name"=>"Meldrum", "scopus_author_id"=>"56485847600"}, {"first_name"=>"Reto", "last_name"=>"Schwendener", "scopus_author_id"=>"7005499188"}, {"first_name"=>"Urs F.", "last_name"=>"Greber", "scopus_author_id"=>"35554733800"}], "year"=>2012, "source"=>"PLoS Pathogens", "identifiers"=>{"pui"=>"365953668", "isbn"=>"1553-7374 (Electronic)\\r1553-7366 (Linking)", "issn"=>"15537366", "doi"=>"10.1371/journal.ppat.1002976", "sgr"=>"84868089514", "scopus"=>"2-s2.0-84868089514", "pmid"=>"23133371"}, "id"=>"e4e37bdf-20d2-3e53-8cda-10084feaedad", "abstract"=>"Viruses use a limited set of host pathways for infection. These pathways represent bona fide antiviral targets with low likelihood of viral resistance. We identified the salicylanilide niclosamide as a broad range antiviral agent targeting acidified endosomes. Niclosamide is approved for human use against helminthic infections, and has anti-neoplastic and antiviral effects. Its mode of action is unknown. Here, we show that niclosamide, which is a weak lipophilic acid inhibited infection with pH-dependent human rhinoviruses (HRV) and influenza virus. Structure-activity studies showed that antiviral efficacy and endolysosomal pH neutralization co-tracked, and acidification of the extracellular medium bypassed the virus entry block. Niclosamide did not affect the vacuolar H(+)-ATPase, but neutralized coated vesicles or synthetic liposomes, indicating a proton carrier mode-of-action independent of any protein target. This report demonstrates that physico-chemical interference with host pathways has broad range antiviral effects, and provides a proof of concept for the development of host-directed antivirals.", "link"=>"http://www.mendeley.com/research/niclosamide-proton-carrier-targets-acidic-endosomes-broad-antiviral-effects", "reader_count"=>50, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>10, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>19, "Student > Postgraduate"=>2, "Student > Master"=>7, "Other"=>1, "Student > Bachelor"=>6, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>10, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>19, "Student > Postgraduate"=>2, "Student > Master"=>7, "Other"=>1, "Student > Bachelor"=>6, "Professor"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>4, "Mathematics"=>2, "Agricultural and Biological Sciences"=>23, "Medicine and Dentistry"=>8, "Pharmacology, Toxicology and Pharmaceutical Science"=>2, "Psychology"=>1, "Chemistry"=>1, "Immunology and Microbiology"=>6}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>8}, "Chemistry"=>{"Chemistry"=>1}, "Psychology"=>{"Psychology"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>6}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>23}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Mathematics"=>{"Mathematics"=>2}, "Unspecified"=>{"Unspecified"=>2}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}}, "reader_count_by_country"=>{"United States"=>1, "Denmark"=>1, "France"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/553503"], "description"=>"<p>A). Time course of niclosamide (12.5 µM) addition and assessment of HRV2 infection of HeLa cells, including DAPI staining for nuclei. B). Quantification of HRV2 and CVB3 infections from panel A with means of infection values including SEM (n = 4). C). Impact of a drug washout on niclosamide efficacy against HRV1A, 16 and CVB3. Cells were pre-incubated with 10 µM of compound for 30 min and either washed three times with PBS or drug. Mean values and SEM of n = 4 are shown relative to DMSO treated control cells. D). Efficacy of BafA1 (50 nM), pleconaril (0.5 µg/ml) and niclosamide (5 µM) added to cells, which had been inoculated with HRV16, 1A or CVB3 for 1, 2 or 3 h at 19°C. Mean infection values and SEM of n = 3 are shown relative to DMSO controls.</p>", "links"=>[], "tags"=>["inhibits"], "article_id"=>224000, "categories"=>["Chemistry", "Cell Biology", "Infectious Diseases"], "users"=>["Andreas Jurgeit", "Robert McDowell", "Stefan Moese", "Eric Meldrum", "Reto Schwendener", "Urs F. Greber"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002976.g002", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Niclosamide_inhibits_virus_entry_post_the_19_176_C_compartment_/224000", "title"=>"Niclosamide inhibits virus entry post the 19°C compartment.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-25 01:06:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/553313"], "description"=>"<p>A). Niclosamide protects HeLa cells from HRV1A, 2, 14 and 16 infections (n = 2), and A549 cells from Influenza A/PR8 (n = 2), while CVB3 (n = 2) and HSV1 (n = 6) infections were not significantly affected, compared to the toxicity effects determined by resazurin measurements. Mean and SEM values are shown, percent relative to DMSO-treated control cells (100%). The inset shows the IC<sub>50</sub> concentrations for half maximal infection inhibitions and the therapeutic indices (TI), defined as the ratio of IC<sub>50</sub>/CC<sub>50</sub>, where CC<sub>50</sub> is the concentration at 50% cell viability. B). Sample images showing the effect of niclosamide on the formation of dsRNA replication centers (mABJ2, Alexa488, green) at 7 h pi. Nuclei are stained with DAPI (blue). Bar = 100 µm.</p>", "links"=>[], "tags"=>["dose-dependent", "inhibitor", "enterovirus", "influenza"], "article_id"=>223803, "categories"=>["Chemistry", "Cell Biology", "Infectious Diseases"], "users"=>["Andreas Jurgeit", "Robert McDowell", "Stefan Moese", "Eric Meldrum", "Reto Schwendener", "Urs F. Greber"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002976.g001", "stats"=>{"downloads"=>2, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Niclosamide_is_a_dose_dependent_inhibitor_of_enterovirus_and_influenza_virus_infections_/223803", "title"=>"Niclosamide is a dose-dependent inhibitor of enterovirus and influenza virus infections.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-25 01:03:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/553734"], "description"=>"<p>A). Ratiometric live cell imaging of acridine orange (AO) green and red fluorescence. Nuclei were stained with Hoechst. B). The mean and SEM values of lysotracker fluorescence from single cell measurements are plotted against niclosamide (µM) and BafA1 (nM) (n = 4) with an overview of lysotracker fluorescence from a 96-well plate. C). Low extracellular pH bypasses niclosamide's antiviral effect. Mean and SEM values of dsRNA-positive cells (n = 2). D). Influence of niclosamide on the distribution of EEA1 (red) or LAMP1 (green) positive endosomes observed in single section confocal micrographs where nuclei (blue) were stained with DAPI and filamentous actin (grey) with phalloidine. E). Quantification of the perinuclear intensity of EEA1 and LAMP1 positive endosomes of cells from automated microscopy and single cell analyses relative to wild type levels (0) with means and SEM (n = 8). F). Electron micrograph of a negatively stained cow brain CCV preparation. G). Percent normalized fluorescence of acridine orange (AO) (excitation 492 nm, emission 540 nm) of control and inhibitor-treated CCV. The 100% signal is equivalent to the DMSO control treated vesicles.</p>", "links"=>[], "tags"=>["neutralizes", "acidic", "endosomal", "ph", "alters"], "article_id"=>224221, "categories"=>["Chemistry", "Cell Biology", "Infectious Diseases"], "users"=>["Andreas Jurgeit", "Robert McDowell", "Stefan Moese", "Eric Meldrum", "Reto Schwendener", "Urs F. Greber"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002976.g003", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Niclosamide_neutralizes_acidic_endosomal_pH_and_alters_the_distribution_of_endosomes_/224221", "title"=>"Niclosamide neutralizes acidic endosomal pH and alters the distribution of endosomes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-25 01:10:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/554293"], "description"=>"<p>Single round infections (a, b) with an overview fluorescence microscopy montage of HeLa cells infected with HRV1A (green) in presence of increasing concentrations of niclosamide, BafA1 or combinations thereof with cell nuclei stained with DAPI (blue). Bar is 100 µm. Viral titer production is indicated in panel (C).</p>", "links"=>[], "tags"=>["antiviral", "efficacy", "niclosamide", "v-atpase", "inhibitor"], "article_id"=>224786, "categories"=>["Chemistry", "Cell Biology", "Infectious Diseases"], "users"=>["Andreas Jurgeit", "Robert McDowell", "Stefan Moese", "Eric Meldrum", "Reto Schwendener", "Urs F. Greber"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002976.g006", "stats"=>{"downloads"=>2, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Synergistic_antiviral_efficacy_of_niclosamide_and_the_v_ATPase_inhibitor_BafA1_/224786", "title"=>"Synergistic antiviral efficacy of niclosamide and the v-ATPase inhibitor BafA1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-25 01:19:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/553939"], "description"=>"<p>A). Efficacy of niclosamide and sixteen structurally related compounds against HRV1A infection of HeLa cells. Infection relative to DMSO treated controls (value 1) and means are indicated (n = 3). Infections and analyses as shown in <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002976#ppat-1002976-g001\" target=\"_blank\">Figure 1</a>. B). Chemical structures of the sixteen niclosamide-related compounds dubbed as TVB compounds. C). Acridine orange (AO) assay for pH-neutralization of endosomal compartments of five TVB compounds with antiviral efficacy. The perinuclear intensity of the red and green AO fluorescence was quantified. Mean and SEM values are shown (n = 2), representing more than 500 cells per condition. D). Overview of green/red ratiometric fluorescence of cells treated with increasing concentrations of indicated compounds. False color images correspond to the data in (c).</p>", "links"=>[], "tags"=>["efficacy", "niclosamide", "compounds", "co-tracks", "endo-lysosomal"], "article_id"=>224427, "categories"=>["Chemistry", "Cell Biology", "Infectious Diseases"], "users"=>["Andreas Jurgeit", "Robert McDowell", "Stefan Moese", "Eric Meldrum", "Reto Schwendener", "Urs F. Greber"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002976.g004", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Antiviral_efficacy_of_niclosamide_related_compounds_co_tracks_with_endo_lysosomal_neutralization_/224427", "title"=>"Antiviral efficacy of niclosamide related compounds co-tracks with endo-lysosomal neutralization.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-25 01:13:47"}
  • {"files"=>["https://ndownloader.figshare.com/files/295039"], "description"=>"<div><p>Viruses use a limited set of host pathways for infection. These pathways represent <em>bona fide</em> antiviral targets with low likelihood of viral resistance. We identified the salicylanilide niclosamide as a broad range antiviral agent targeting acidified endosomes. Niclosamide is approved for human use against helminthic infections, and has anti-neoplastic and antiviral effects. Its mode of action is unknown. Here, we show that niclosamide, which is a weak lipophilic acid inhibited infection with pH-dependent human rhinoviruses (HRV) and influenza virus. Structure-activity studies showed that antiviral efficacy and endolysosomal pH neutralization co-tracked, and acidification of the extracellular medium bypassed the virus entry block. Niclosamide did not affect the vacuolar H<sup>+</sup>-ATPase, but neutralized coated vesicles or synthetic liposomes, indicating a proton carrier mode-of-action independent of any protein target. This report demonstrates that physico-chemical interference with host pathways has broad range antiviral effects, and provides a proof of concept for the development of host-directed antivirals.</p> </div>", "links"=>[], "tags"=>["niclosamide", "proton", "targets", "acidic", "endosomes", "antiviral", "effects"], "article_id"=>118105, "categories"=>["Chemistry", "Cancer", "Cell Biology"], "users"=>["Andreas Jurgeit", "Robert McDowell", "Stefan Moese", "Eric Meldrum", "Reto Schwendener", "Urs F. Greber"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002976", "stats"=>{"downloads"=>3, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Niclosamide_Is_a_Proton_Carrier_and_Targets_Acidic_Endosomes_with_Broad_Antiviral_Effects__/118105", "title"=>"Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral Effects", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-10-25 02:15:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/554112"], "description"=>"<p>A). 200 nm sized liposomes were prepared in presence of dextran-FITC (1 mM, 4.4 kDa) at pH 5.15 (top panel), which quenches FITC-fluorescence and dequenched by the protonophoric action of niclosamide, 2,4-DNP (2,4-di-nitrophenol) or m-CCCP (m-chlorophenylhydrazone). The integrity of liposomes upon treatment is shown as mean vesicle size (insert bar-graph). B). Model of the protonophore mode of action of niclosamide. Niclosamide readily passes through biological membranes due to its lipophilic nature, as indicated by log P = 4.48 at pH 7.0 <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002976#ppat.1002976-Anonymous1\" target=\"_blank\">[33]</a>. Niclosamide (pKa of 5.6) is protonated in the acidic compartment of endosomes, and thereby increases its lipophilicity (log P = 5.63 at pH 5.7). This may enhance its partitioning into the lipid bilayer. In the pH-neutral cytosol a proton dissociates and the compound can interact again with membranes to repeat the cycle. Note that the location of the proposed negative charge on niclosamide is not known.</p>", "links"=>[], "tags"=>["neutralizes", "acidic", "liposomal", "ph", "gradient", "uncoupling", "agents", "dnp"], "article_id"=>224594, "categories"=>["Chemistry", "Cell Biology", "Infectious Diseases"], "users"=>["Andreas Jurgeit", "Robert McDowell", "Stefan Moese", "Eric Meldrum", "Reto Schwendener", "Urs F. Greber"], "doi"=>"https://dx.doi.org/10.1371/journal.ppat.1002976.g005", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Niclosamide_neutralizes_acidic_liposomal_pH_similar_as_the_protein_gradient_uncoupling_agents_DNP_or_CCCP_/224594", "title"=>"Niclosamide neutralizes acidic liposomal pH similar as the protein gradient uncoupling agents DNP or CCCP.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-25 01:16:34"}

PMC Usage Stats | Further Information

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Relative Metric

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