Potent Host-Directed Small-Molecule Inhibitors of Myxovirus RNA-Dependent RNA-Polymerases
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{"title"=>"Potent host-directed small-molecule inhibitors of myxovirus rna-dependent rna-polymerases", "type"=>"journal", "authors"=>[{"first_name"=>"Stefanie A.", "last_name"=>"Krumm", "scopus_author_id"=>"34880398200"}, {"first_name"=>"J. Maina", "last_name"=>"Ndungu", "scopus_author_id"=>"6603207005"}, {"first_name"=>"Jeong Joong", "last_name"=>"Yoon", "scopus_author_id"=>"14072099000"}, {"first_name"=>"Melanie", "last_name"=>"Dochow", "scopus_author_id"=>"53363357500"}, {"first_name"=>"Aiming", "last_name"=>"Sun", "scopus_author_id"=>"8267147200"}, {"first_name"=>"Michael", "last_name"=>"Natchus", "scopus_author_id"=>"6602539833"}, {"first_name"=>"James P.", "last_name"=>"Snyder", "scopus_author_id"=>"7401498863"}, {"first_name"=>"Richard K.", "last_name"=>"Plemper", "scopus_author_id"=>"6602156111"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-79956125738", "doi"=>"10.1371/journal.pone.0020069", "pui"=>"361783696", "issn"=>"19326203", "pmid"=>"21603574", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "sgr"=>"79956125738"}, "id"=>"a274acfc-d8a4-3950-83f5-90f3caebdc6c", "abstract"=>"Therapeutic targeting of host cell factors required for virus replication rather than of pathogen components opens new perspectives to counteract virus infections. Anticipated advantages of this approach include a heightened barrier against the development of viral resistance and a broadened pathogen target spectrum. Myxoviruses are predominantly associated with acute disease and thus are particularly attractive for this approach since treatment time can be kept limited. To identify inhibitor candidates, we have analyzed hit compounds that emerged from a large-scale high-throughput screen for their ability to block replication of members of both the orthomyxovirus and paramyxovirus families. This has returned a compound class with broad anti-viral activity including potent inhibition of different influenza virus and paramyxovirus strains. After hit-to-lead chemistry, inhibitory concentrations are in the nanomolar range in the context of immortalized cell lines and human PBMCs. The compound shows high metabolic stability when exposed to human S-9 hepatocyte subcellular fractions. Antiviral activity is host-cell species specific and most pronounced in cells of higher mammalian origin, supporting a host-cell target. While the compound induces a temporary cell cycle arrest, host mRNA and protein biosynthesis are largely unaffected and treated cells maintain full metabolic activity. Viral replication is blocked at a post-entry step and resembles the inhibition profile of a known inhibitor of viral RNA-dependent RNA-polymerase (RdRp) activity. Direct assessment of RdRp activity in the presence of the reagent reveals strong inhibition both in the context of viral infection and in reporter-based minireplicon assays. In toto, we have identified a compound class with broad viral target range that blocks host factors required for viral RdRp activity. Viral adaptation attempts did not induce resistance after prolonged exposure, in contrast to rapid adaptation to a pathogen-directed inhibitor of RdRp activity.", "link"=>"http://www.mendeley.com/research/potent-hostdirected-smallmolecule-inhibitors-myxovirus-rnadependent-rnapolymerases", "reader_count"=>15, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>4, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>1, "Student > Master"=>1, "Other"=>1, "Student > Bachelor"=>4}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>4, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>1, "Student > Master"=>1, "Other"=>1, "Student > Bachelor"=>4}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>7, "Medicine and Dentistry"=>1, "Chemistry"=>3, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Chemistry"=>{"Chemistry"=>3}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>7}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"France"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/388804", "https://ndownloader.figshare.com/files/388870"], "description"=>"<div><p>Therapeutic targeting of host cell factors required for virus replication rather than of pathogen components opens new perspectives to counteract virus infections. Anticipated advantages of this approach include a heightened barrier against the development of viral resistance and a broadened pathogen target spectrum. Myxoviruses are predominantly associated with acute disease and thus are particularly attractive for this approach since treatment time can be kept limited. To identify inhibitor candidates, we have analyzed hit compounds that emerged from a large-scale high-throughput screen for their ability to block replication of members of both the orthomyxovirus and paramyxovirus families. This has returned a compound class with broad anti-viral activity including potent inhibition of different influenza virus and paramyxovirus strains. After hit-to-lead chemistry, inhibitory concentrations are in the nanomolar range in the context of immortalized cell lines and human PBMCs. The compound shows high metabolic stability when exposed to human S-9 hepatocyte subcellular fractions. Antiviral activity is host-cell species specific and most pronounced in cells of higher mammalian origin, supporting a host-cell target. While the compound induces a temporary cell cycle arrest, host mRNA and protein biosynthesis are largely unaffected and treated cells maintain full metabolic activity. Viral replication is blocked at a post-entry step and resembles the inhibition profile of a known inhibitor of viral RNA-dependent RNA-polymerase (RdRp) activity. Direct assessment of RdRp activity in the presence of the reagent reveals strong inhibition both in the context of viral infection and in reporter-based minireplicon assays. <em>In toto</em>, we have identified a compound class with broad viral target range that blocks host factors required for viral RdRp activity. Viral adaptation attempts did not induce resistance after prolonged exposure, in contrast to rapid adaptation to a pathogen-directed inhibitor of RdRp activity.</p> </div>", "links"=>[], "tags"=>["potent", "host-directed", "small-molecule", "inhibitors", "myxovirus", "rna-dependent", "rna-polymerases"], "article_id"=>136766, "categories"=>["Cancer", "Pharmacology"], "users"=>["Stefanie A. Krumm", "J. Maina Ndungu", "Jeong-Joong Yoon", "Melanie Dochow", "Aiming Sun", "Michael Natchus", "James P. Snyder", "Richard K. Plemper"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0020069.s001", "https://dx.doi.org/10.1371/journal.pone.0020069.s002"], "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Potent_Host_Directed_Small_Molecule_Inhibitors_of_Myxovirus_RNA_Dependent_RNA_Polymerases/136766", "title"=>"Potent Host-Directed Small-Molecule Inhibitors of Myxovirus RNA-Dependent RNA-Polymerases", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2011-05-16 01:52:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/775057"], "description"=>"a<p>For influenza virus titration, genome copy numbers of released progeny particles were quantified by TaqMan RT-PCR.</p>b<p>Titered through plaque assaying.</p>c<p>Titered by TCID<sub>50</sub> titration.</p>d<p>Highest concentration assessed 75 µM.</p>e<p>95% confidence interval.</p><p>ND: not determined.</p>", "links"=>[], "tags"=>["vero-slam", "concentrations", "jmn3-003", "clinically", "para-", "orthomyxovirus", "members", "mev-specific", "inhibitor", "viral", "rdrp"], "article_id"=>445403, "categories"=>["Virology", "Pharmacology"], "users"=>["Stefanie A. Krumm", "J. Maina Ndungu", "Jeong-Joong Yoon", "Melanie Dochow", "Aiming Sun", "Michael Natchus", "James P. Snyder", "Richard K. Plemper"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0020069.t001", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Active_EC_50_and_toxic_CC_50_determined_on_Vero_Slam_cells_concentrations_of_JMN3_003_against_a_selection_of_clinically_relevant_para_and_orthomyxovirus_family_members_in_comparison_with_active_concentrations_of_AS_136A_a_previously_characterized_MeV_spe/445403", "title"=>"Active (EC<sub>50</sub>) and toxic (CC<sub>50</sub>, determined on Vero-Slam cells) concentrations of JMN3-003 against a selection of clinically relevant para- and orthomyxovirus family members in comparison with active concentrations of AS-136A, a previously characterized, MeV-specific inhibitor of the viral RdRp complex [20], [36].", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-05-16 01:30:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/774605"], "description"=>"<p><b>A</b>) Incubation of the article with human liver S9 fractions for up to 60 minutes, followed by LC-MS/MS analysis of the material remaining. Two analogs of JMN3-003, JMN5-165 and JMN5-166 (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0020069#pone.0020069.s001\" target=\"_blank\">figure S1</a>), showed little stability and are included for comparison. Values represent averages of 2 replicates, calculated half-lives (t<sub>1/2</sub>) are given in the figure captures. <b>B</b>) Incubation of JMN3-003 for up to 120 minutes with human plasma derived from mixed, healthy donors, followed by LC-MS/MS quantification of the material remaining. Unstable procaine and stable procainamide were examined equally for comparison. Values represent averages of three experiments ± SD.</p>", "links"=>[], "tags"=>["jmn3-003", "scaffold", "metabolically"], "article_id"=>444969, "categories"=>["Virology", "Pharmacology"], "users"=>["Stefanie A. Krumm", "J. Maina Ndungu", "Jeong-Joong Yoon", "Melanie Dochow", "Aiming Sun", "Michael Natchus", "James P. Snyder", "Richard K. Plemper"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0020069.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_JMN3_003_scaffold_is_metabolically_stable_in_vitro_/444969", "title"=>"The JMN3-003 scaffold is metabolically stable <i>in vitro</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-16 01:22:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/775001"], "description"=>"a<p>titers of progeny virus grown on the different cell lines in the presence of vehicle (DMSO) only were determined through plaque assays on MDCK cells.</p>b<p>EC<sub>50</sub> concentrations were determined based on four parameter non-linear regression models generated for individual dose-response curves.</p>c<p>Highest concentration assessed 75 µM.</p><p>Active concentrations (EC<sub>50</sub>) of JMN3-003 against influenza A/WSN propagated on a variety of different host cell lines.</p>", "links"=>[], "tags"=>["jmn3-003"], "article_id"=>445370, "categories"=>["Virology", "Pharmacology"], "users"=>["Stefanie A. Krumm", "J. Maina Ndungu", "Jeong-Joong Yoon", "Melanie Dochow", "Aiming Sun", "Michael Natchus", "James P. Snyder", "Richard K. Plemper"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0020069.t002", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Antiviral_activity_of_JMN3_003_is_host_cell_species_specific_/445370", "title"=>"Antiviral activity of JMN3-003 is host cell species-specific.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-05-16 01:29:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/774553"], "description"=>"<p>Dose-response curves for MeV-Alaska grown in the presence of JMN3-003 on human PBMCs originating from a mixed pool of healthy donors. Vero-Slam cell-based inhibition curves are shown for comparison. Values reflect averages of three replicates. EC<sub>50</sub> concentrations ± SD are derived from four-parameter non-linear regression modeling.</p>", "links"=>[], "tags"=>["cellular", "jmn3-003", "extends"], "article_id"=>444917, "categories"=>["Virology", "Pharmacology"], "users"=>["Stefanie A. Krumm", "J. Maina Ndungu", "Jeong-Joong Yoon", "Melanie Dochow", "Aiming Sun", "Michael Natchus", "James P. Snyder", "Richard K. Plemper"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0020069.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_cellular_target_range_of_JMN3_003_extends_to_primary_human_cells_/444917", "title"=>"The cellular target range of JMN3-003 extends to primary human cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-16 01:21:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/774952"], "description"=>"<p>MeV-Alaska remains sensitive to the compound after continued adaptation events for a 90-day period, while resistance (extensive viral CPE detectable in the presence of 30 µM compound) to pathogen-directed AS-136A emerges in step-wise adaptations after 15–25 days. Three independent adaptations (represented by solid, dotted and dashed lines, respectively) were pursued for each compound.</p>", "links"=>[], "tags"=>["prohibits", "emergence", "viral"], "article_id"=>445314, "categories"=>["Virology", "Pharmacology"], "users"=>["Stefanie A. Krumm", "J. Maina Ndungu", "Jeong-Joong Yoon", "Melanie Dochow", "Aiming Sun", "Michael Natchus", "James P. Snyder", "Richard K. Plemper"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0020069.g008", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_JMN3_003_prohibits_rapid_emergence_of_viral_resistance_in_vitro_/445314", "title"=>"JMN3-003 prohibits rapid emergence of viral resistance <i>in vitro</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-16 01:28:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/774737"], "description"=>"<p><b>A</b>) Relative TaqMan RT-PCR-based quantitation of three unstable cellular mRNAs (MCL1, ASB7, MKP-1) after exposure of cells to JMN3-003 for six hours. Controls were treated with Actinomycine D (Act D) for comparison. C<sub>T</sub> values are expressed relative to vehicle-treated samples and reflect averages of three independent experiments, each analyzed in triplicate, ± SD. <b>B–D</b>) Expression of virus-encoded but not host cell or plasmid-encoded viral proteins is blocked by JMN3-003. Immunodetection of transiently expressed MeV-F (<b>B</b>), virus-encoded MeV-F (<b>C</b>), and virus-encoded influenza A/WSN M2 (<b>D</b>) in cell lysates after incubation of cells in the presence of compound or vehicle only (DMSO) for 30 hours. As internal cellular standard, membranes were probed for GAPDH in parallel. Numbers correspond to average densitometric quantitations ± SD of three experiments, representative immunoblots are shown. (ND: not determined).</p>", "links"=>[], "tags"=>["mrna", "synthesis", "unaffected"], "article_id"=>445103, "categories"=>["Virology", "Pharmacology"], "users"=>["Stefanie A. Krumm", "J. Maina Ndungu", "Jeong-Joong Yoon", "Melanie Dochow", "Aiming Sun", "Michael Natchus", "James P. Snyder", "Richard K. Plemper"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0020069.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Host_cell_mRNA_synthesis_and_translation_are_unaffected_by_compound_JMN3_003_/445103", "title"=>"Host cell mRNA synthesis and translation are unaffected by compound JMN3-003.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-16 01:25:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/774483"], "description"=>"<p>Chemical structures of the identified scaffold (<b>A</b>) and the current lead analog JMN3-003 (<b>B</b>). <b>C</b>) Dose-response curves for JMN3-003 and MeV-Alaska, MuV-South Africa, RSV Long, influenza A/WSN (H1N1), sindbis virus and vaccinia virus. Titers of cell-associated progeny viruses were determined by TCID<sub>50</sub> titration (MeV) or plaque assay (MuV, RSV, sindbis virus, vaccinia virus). For influenza virus, genome copy numbers of released progeny particles were quantified through TaqMan RT-PCR. Titers of released sindbis virus particles were determined by plaque assay. Values reflect averages of at least three experiments ± SD, vaccinia virus titers were determined in duplicate. <b>D and E</b>) Assessment of metabolic activity of cells after incubation of different established cell lines (D) or primary human cells (E) in the presence of JMN3-003 for 24 hours. Results for human (HeLa, A549, HepG2), primate (Vero-Slam), and canine (MDCK) cell lines and primary human cells (PBMC, smooth muscle, bronchial epithelial) are shown. Values reflect averages of four replicates ± SD.</p>", "links"=>[], "tags"=>["scaffold", "anti-myxovirus"], "article_id"=>444853, "categories"=>["Virology", "Pharmacology"], "users"=>["Stefanie A. Krumm", "J. Maina Ndungu", "Jeong-Joong Yoon", "Melanie Dochow", "Aiming Sun", "Michael Natchus", "James P. Snyder", "Richard K. Plemper"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0020069.g001", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Identification_of_a_chemical_scaffold_with_broad_anti_myxovirus_activity_/444853", "title"=>"Identification of a chemical scaffold with broad anti-myxovirus activity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-16 01:20:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/774656"], "description"=>"<p><b>A</b>) FACS analysis of acridine orange-stained HeLa cells incubated in the presence of JMN3-003 or hydroxyurea for 36 hours, or nocodazole for 16 hours. Dark grey shaded areas show unstained cells, light grey areas correspond to vehicle-treated control cells, and areas under open black curves represent treated cell populations. Dashed vertical lines indicate 2 N (G<sub>1</sub>/S) and 4N (G<sub>2</sub>/M) DNA contents. Data shown are representative of three experiments and reflect 10,000 events/condition of treatment. <b>B</b>) Analysis of the phosphorylation status of cdc2-cyclin B kinase after cell exposure to JMN3-003 through immunoblotting using specific antisera directed against phospho-cdc2 (Tyr15; α cdc2-P) or total cdc2 (α cdc2) for comparison. For control, cells were treated with nocodazole, hydroxyurea, or alsterpaullone (right panel). Results shown are representative of multiple experiments. <b>C</b>) Wash-out of JMN3-003 restores cell proliferation. Growth rates of Vero cells were determined after 30-hour exposure of cells to JMN3-003 or vehicle only, followed by wash-out of the substance. Values reflect cell divisions per day and are based on averages of six independent replicate experiments ± SEM. <b>D</b>) G<sub>1</sub>/S phase cell cycle arrest does not affect MeV proliferation <i>per se</i>. Dose-response curves for alsterpaullone, a nanomolar CDK1/cyclin B kinase inhibitor, and MeV-Alaska grown on Vero-Slam cell. Titers of cell-associated viral particles were determined 36 hours post-infection through TCID<sub>50</sub> titration. JMN3-003 was examined in parallel for comparison. Values reflect averages of three replicates ± SD.</p>", "links"=>[], "tags"=>["jmn3-003", "induces"], "article_id"=>445023, "categories"=>["Virology", "Pharmacology"], "users"=>["Stefanie A. Krumm", "J. Maina Ndungu", "Jeong-Joong Yoon", "Melanie Dochow", "Aiming Sun", "Michael Natchus", "James P. Snyder", "Richard K. Plemper"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0020069.g004", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cell_exposure_to_compound_JMN3_003_induces_a_temporary_G_1_S_phase_cell_cycle_arrest_/445023", "title"=>"Cell exposure to compound JMN3-003 induces a temporary G<sub>1</sub>/S phase cell cycle arrest.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-16 01:23:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/774901"], "description"=>"<p><b>A</b>) Relative quantitations of MeV F mRNA and antigenome (+RNA) levels after incubation of infected cells in the presence of compound for 40 hours. Samples were normalized for vehicle only (DMSO)-treated cells and ΔΔC<sub>T</sub> values calculated using cellular GAPDH as reference. Mock samples remained uninfected. Averages of three independent experiments, assessed in triplicate each, ± SD are shown. <b>B</b>) Quantitation of influenza A/WSN segment seven antigenome (+RNA) and of released progeny genomic RNA (genome copies) after incubation of infected MDCK cells in the presence of compound for 24 hours. For +RNA quantitation, samples were normalized and ΔΔC<sub>T</sub> values calculated as outlined in (A). Released genome copies were quantified by TaqMan RT-PCR relative to an external standard, then normalized for vehicle-treated controls. Averages of four experiments, assessed in triplicate each, ± SD are shown. <b>C</b>) Luciferase reporter-based assessment of viral RdRp activity in the presence of JMN3-003. BHK-T7 cells transfected with plasmids encoding the MeV minireplicon reporter system were incubated in the presence of JMN3-003 or vehicle only for 36 hours. Values were normalized for luciferase activities found in vehicle (DMSO)-treated controls and represent averages of three experiments assessed in duplicate each ± SD.</p>", "links"=>[], "tags"=>["jmn3-003", "inhibits", "viral", "rna"], "article_id"=>445266, "categories"=>["Virology", "Pharmacology"], "users"=>["Stefanie A. Krumm", "J. Maina Ndungu", "Jeong-Joong Yoon", "Melanie Dochow", "Aiming Sun", "Michael Natchus", "James P. Snyder", "Richard K. Plemper"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0020069.g007", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Compound_JMN3_003_inhibits_viral_RNA_synthesis_/445266", "title"=>"Compound JMN3-003 inhibits viral RNA synthesis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-16 01:27:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/774818"], "description"=>"<p><b>A–B</b>) Cell-to-cell fusion is unaffected by the compound. Microphotographs of MeV-H and F expressing Vero-Slam cells (<b>A</b>) and quantitative cell-to-cell fusion assays (<b>B</b>) show membrane fusion activities in the presence of JMN3-003 similar to those observed for vehicle (DMSO)-treated controls. The effect of fusion inhibitory peptide (FIP) is shown in (B) for comparison. <b>C</b>) JMN3-003 antiviral activity is reversible and not based on cell priming. Vero-Slam cells were pre-treated with 1.0 µM JMN3-003 for 60 minutes, followed by compound wash-out and incubation for the indicated time periods; at t<sub>0</sub>, cells were infected with MeV-Alaska. <b>D</b>) JMN3-003 lacks virucidal activity. MeV-Alaska particles were incubated with 1.0 µM JMN3-003 for 60 minutes, followed by dilution of compound to 1.0 nM and infection of cells at an MOI of 0.033 in the presence of vehicle (JMN3-003/infect./DMSO). Equally treated controls received vehicle only (DMSO/infect./DMSO), compound only after infection (DMSO/infect./JMN3-003), or compound for the duration of the experiment (JMN3-003/infect./JMN3-003). <b>E</b>) Addition of JMN3-003 (1.0 µM final concentration) at the indicated times post-infection of cells with MeV-Alaska. For comparison, inhibition profiles of the MeV entry inhibitor AS-48 (75 µM) and RdRp blocker AS-136A (25 µM) are shown. Controls received vehicle only (DMSO) at the time of infection. For (C–E), values show titers of cell associated viral particles (TCID<sub>50</sub>/ml) and represent averages of at least three experiments ± SD.</p>", "links"=>[], "tags"=>["time-of-addition", "jmn3-003", "shows", "inhibition", "rdrp"], "article_id"=>445183, "categories"=>["Virology", "Pharmacology"], "users"=>["Stefanie A. Krumm", "J. Maina Ndungu", "Jeong-Joong Yoon", "Melanie Dochow", "Aiming Sun", "Michael Natchus", "James P. Snyder", "Richard K. Plemper"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0020069.g006", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_time_of_addition_assays_JMN3_003_shows_the_inhibition_profile_of_an_RdRp_blocker_/445183", "title"=>"In time-of-addition assays, JMN3-003 shows the inhibition profile of an RdRp blocker.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-05-16 01:26:23"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"6", "full-text"=>"6", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"11"}
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  • {"unique-ip"=>"2", "full-text"=>"1", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"8"}
  • {"unique-ip"=>"9", "full-text"=>"7", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2018", "month"=>"11"}
  • {"unique-ip"=>"10", "full-text"=>"13", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"9"}
  • {"unique-ip"=>"9", "full-text"=>"9", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"12"}
  • {"unique-ip"=>"10", "full-text"=>"12", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
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  • {"unique-ip"=>"5", "full-text"=>"4", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"8", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"11", "full-text"=>"11", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}
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Relative Metric

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