A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity
Publication Date
July 25, 2013
Journal
PLOS Pathogens
Authors
Jan Balzarini, Graciela Andrei, Emanuela Balestra, Dana Huskens, et al
Volume
9
Issue
7
Pages
e1003456
DOI
https://dx.plos.org/10.1371/journal.ppat.1003456
Publisher URL
http://journals.plos.org/plospathogens/article?id=10.1371%2Fjournal.ppat.1003456
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/23935482
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723632
Europe PMC
http://europepmc.org/abstract/MED/23935482
Web of Science
000322316700015
Scopus
84884794379
Mendeley
http://www.mendeley.com/research/multitargeted-drug-candidate-dual-antihiv-antihsv-activity
Events
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Mendeley | Further Information

{"title"=>"A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity", "type"=>"journal", "authors"=>[{"first_name"=>"Jan", "last_name"=>"Balzarini", "scopus_author_id"=>"36049696300"}, {"first_name"=>"Graciela", "last_name"=>"Andrei", "scopus_author_id"=>"21833714800"}, {"first_name"=>"Emanuela", "last_name"=>"Balestra", "scopus_author_id"=>"7004639871"}, {"first_name"=>"Dana", "last_name"=>"Huskens", "scopus_author_id"=>"16052693800"}, {"first_name"=>"Christophe", "last_name"=>"Vanpouille", "scopus_author_id"=>"6507734655"}, {"first_name"=>"Andrea", "last_name"=>"Introini", "scopus_author_id"=>"49461298200"}, {"first_name"=>"Sonia", "last_name"=>"Zicari", "scopus_author_id"=>"54895652900"}, {"first_name"=>"Sandra", "last_name"=>"Liekens", "scopus_author_id"=>"6602578682"}, {"first_name"=>"Robert", "last_name"=>"Snoeck", "scopus_author_id"=>"7004330504"}, {"first_name"=>"Antonín", "last_name"=>"Holý", "scopus_author_id"=>"7102280650"}, {"first_name"=>"Carlo Federico", "last_name"=>"Perno", "scopus_author_id"=>"35380302400"}, {"first_name"=>"Leonid", "last_name"=>"Margolis", "scopus_author_id"=>"7102677602"}, {"first_name"=>"Dominique", "last_name"=>"Schols", "scopus_author_id"=>"7007182334"}], "year"=>2013, "source"=>"PLoS Pathogens", "identifiers"=>{"issn"=>"15537366", "pui"=>"369919420", "doi"=>"10.1371/journal.ppat.1003456", "sgr"=>"84884794379", "scopus"=>"2-s2.0-84884794379", "isbn"=>"1553-7374 (Electronic)\r1553-7366 (Linking)", "pmid"=>"23935482"}, "id"=>"1b6bf482-b6f6-3578-bd81-0e70e27a5ca3", "abstract"=>"Human immunodeficiency virus (HIV) infection is often accompanied by infection with other pathogens, in particular herpes simplex virus type 2 (HSV-2). The resulting coinfection is involved in a vicious circle of mutual facilitations. Therefore, an important task is to develop a compound that is highly potent against both viruses to suppress their transmission and replication. Here, we report on the discovery of such a compound, designated PMEO-DAPym. We compared its properties with those of the structurally related and clinically used acyclic nucleoside phosphonates (ANPs) tenofovir and adefovir. We demonstrated the potent anti-HIV and -HSV activity of this drug in a diverse set of clinically relevant in vitro, ex vivo, and in vivo systems including (i) CD4⁺ T-lymphocyte (CEM) cell cultures, (ii) embryonic lung (HEL) cell cultures, (iii) organotypic epithelial raft cultures of primary human keratinocytes (PHKs), (iv) primary human monocyte/macrophage (M/M) cell cultures, (v) human ex vivo lymphoid tissue, and (vi) athymic nude mice. Upon conversion to its diphosphate metabolite, PMEO-DAPym markedly inhibits both HIV-1 reverse transcriptase (RT) and HSV DNA polymerase. However, in striking contrast to tenofovir and adefovir, it also acts as an efficient immunomodulator, inducing β-chemokines in PBMC cultures, in particular the CCR5 agonists MIP-1β, MIP-1α and RANTES but not the CXCR4 agonist SDF-1, without the need to be intracellularly metabolized. Such specific β-chemokine upregulation required new mRNA synthesis. The upregulation of β-chemokines was shown to be associated with a pronounced downmodulation of the HIV-1 coreceptor CCR5 which may result in prevention of HIV entry. PMEO-DAPym belongs conceptually to a new class of efficient multitargeted antivirals for concomitant dual-viral (HSV/HIV) infection therapy through inhibition of virus-specific pathways (i.e. the viral polymerases) and HIV transmission prevention through interference with host pathways (i.e. CCR5 receptor down regulation).", "link"=>"http://www.mendeley.com/research/multitargeted-drug-candidate-dual-antihiv-antihsv-activity", "reader_count"=>19, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>3, "Student > Master"=>2, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>3, "Student > Master"=>2, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Mathematics"=>1, "Agricultural and Biological Sciences"=>2, "Medicine and Dentistry"=>4, "Chemistry"=>6, "Immunology and Microbiology"=>3}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Chemistry"=>{"Chemistry"=>6}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>2}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>3}}, "reader_count_by_country"=>{"Netherlands"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1130949"], "description"=>"<p>Adefovir and tenofovir are purine (adenine) analogues. PMEO-DAPym is a (2,4-diamino)pyrimidine analogue <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003456#ppat.1003456-Balzarini3\" target=\"_blank\">[46]</a>, <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003456#ppat.1003456-Hol1\" target=\"_blank\">[47]</a>. Molecular modeling revealed that the PMEO-derivatives are structural mimics of the corresponding purine (2-aminoadenine) analogues <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003456#ppat.1003456-Ying1\" target=\"_blank\">[53]</a>, and it was recently shown that PMEO-DAPym also functionally behaves as an adenine analogue like adefovir and tenofovir <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003456#ppat.1003456-Herman1\" target=\"_blank\">[54]</a>.</p>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "formulae", "acyclic", "nucleoside"], "article_id"=>755029, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Structural_formulae_of_the_acyclic_nucleoside_phosphonates_/755029", "title"=>"Structural formulae of the acyclic nucleoside phosphonates.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 02:07:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1130951"], "description"=>"<p>Confluent HEL cell cultures were exposed to 100 TCID<sub>50</sub> of clinical virus isolates [wild-type HSV-1 (panel A), wild-type HSV-2 (panel B), TK<sup>−</sup> HSV-1 (panel C) and TK<sup>−</sup> HSV-2 (panel D)] in the presence of drugs at different concentrations and incubated for 3 days at 37°C. Then, the cytopathicity was determined microscopically and the EC<sub>50</sub> values determined. <sup>a</sup>EC<sub>50</sub>, 50% effective concentration or compound concentration required to reduce virus-induced cytopathicity (CPE) by 50%. Data shown are the means of at least two independent experiments. The HSV-1, HSV-2, HSV-1 TK<sup>−</sup>, and HSV-2 TK<sup>−</sup> clinical isolates have been described in reference 19, including the nature of the mutations in the TK gene of the acyclovir-resistant virus strains.</p>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "compounds"], "article_id"=>755031, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Antiherpetic_activity_of_test_compounds_in_cell_culture_/755031", "title"=>"Antiherpetic activity of test compounds in cell culture.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 02:07:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1130952"], "description"=>"<p>Panels <b>A</b> (HSV-1) and <b>B</b> (HSV-2): Drugs at different concentrations were added to the raft cell cultures on the day of infection (10 days after initiation of differentiation). The drugs remained in the presence of the cells for 5 days until the rafts were frozen for determination of virus production with a plaque assay in HEL cell cultures. Error bars represent S.D.</p>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "activities", "pmeo-dapym", "hsv-1", "hsv-2", "strains", "organotypic", "epithelial", "raft"], "article_id"=>755032, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibitory_activities_of_tenofovir_adefovir_and_PMEO_DAPym_against_laboratory_HSV_1_and_HSV_2_strains_in_organotypic_epithelial_raft_cultures_/755032", "title"=>"Inhibitory activities of tenofovir, adefovir, and PMEO-DAPym against laboratory HSV-1 and HSV-2 strains in organotypic epithelial raft cultures.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 02:07:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1130955"], "description"=>"<p>Different PMEO-DAPym concentrations were exposed to several wild-type clinical HSV-1 (RV-174) and HSV-2 (NS and RV-194) isolates in HEL cell cultures at different multiplicities of infection (m.o.i.; 10<sup>−3</sup> (left graph) or 10<sup>−4</sup> (right graph)). Virus yield was determined at 24, 48, and 72 h post infection, and EC<sub>90</sub> and EC<sub>99</sub> values were calculated from the graphical plots. Error bars represent S.D.</p>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "pmeo-dapym", "hsv", "isolates", "hel"], "article_id"=>755035, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibitory_activity_of_PMEO_DAPym_against_clinical_HSV_isolates_in_HEL_cell_cultures_/755035", "title"=>"Inhibitory activity of PMEO-DAPym against clinical HSV isolates in HEL cell cultures.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 02:07:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1130956"], "description"=>"<p>Blocks of human tonsillar tissue were inoculated <i>ex vivo</i> with HSV-2 (G) and treated or not with adefovir or PMEO-DAPym. We monitored HSV-2 (G) replication by measuring viral DNA in culture media at different times throughout the culture period. Presented are means ± SEM of cumulative HSV-2 (G) replication in tissues from two to six donors. For each donor, data represent pooled viral release from 27 tissue blocks.</p>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "hsv-2", "infected", "tonsillar", "adefovir"], "article_id"=>755036, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Suppression_of_HSV_2_in_infected_human_ex_vivo_tonsillar_tissue_by_adefovir_and_PMEO_DAPym_/755036", "title"=>"Suppression of HSV-2 in infected human <i>ex vivo</i> tonsillar tissue by adefovir and PMEO-DAPym.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 02:07:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1130958"], "description"=>"<p>Blocks of human cervico-vaginal tissues were inoculated <i>ex vivo</i> with HSV-2 (G) or co-infected with HIV-1 and HSV-2 and treated or not with adefovir (1 µg/ml) or PMEO-DAPym (1 µg/ml). We monitored HSV-2 (G) replication by measuring viral DNA accumulated in culture media at different times throughout the culture period. Presented is cumulative HSV-2 (G) replication, with data representing pooled viral release from 16 tissue blocks.</p>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "hsv-2", "cervico-vaginal", "tissues", "adefovir"], "article_id"=>755038, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.g006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Suppression_of_HSV_2_in_human_cervico_vaginal_tissues_by_adefovir_and_PMEO_DAPym_/755038", "title"=>"Suppression of HSV-2 in human cervico-vaginal tissues by adefovir and PMEO-DAPym.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 02:07:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1130959"], "description"=>"<p>Panels A and B: Blocks of human tonsillar tissue from five different donors were co-inoculated <i>ex vivo</i> with HSV-2 (G) and HIV-1 (LAI) and treated or not with adefovir or PMEO-DAPym (1 µg/ml). For tissue from each donor, we monitored replication of both viruses by evaluating their accumulation in the culture media bathing 27 tissue blocks at different times throughout the culture. We evaluated HIV-1 replication by measuring p24<sub>gag</sub> and HSV-2 (G) replication by measuring HSV-2 viral DNA. Panel <b>A</b>: Presented are kinetics of HSV-2 (G) and HIV-1 (LAI) replication (insert). Each point represents the mean ± SEM of viral replication in tissues from five donors. Panel <b>B</b>: Presented are means ± SEM of cumulative HSV-2 (G) and HIV-1 (LAI) replication (insert).</p>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "hsv-2", "single-infected", "hiv-1", "co-infected", "tonsillar", "adefovir"], "article_id"=>755039, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.g007"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Suppression_of_HSV_2_in_single_infected_and_HIV_1_co_infected_human_ex_vivo_tonsillar_tissue_by_adefovir_and_PMEO_DAPym_/755039", "title"=>"Suppression of HSV-2 in single-infected and HIV-1 co-infected human <i>ex vivo</i> tonsillar tissue by adefovir and PMEO-DAPym.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 02:07:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1130961"], "description"=>"<p>Groups of five nu/nu mice were inoculated with HSV-1 (panel A) or HSV-2 (panel B) on the lumbosacral area. Each cohort was then subjected to topical treatment twice daily for 5 consecutive days, starting on the day of viral infection. The placebo groups received a similar treatment with the test formulation without drug. Mortality was recorded over a period of 30 days. Animals were euthanized when more than 30% loss in body weight or development of paralysis occurred. We estimated survival rates according to the Kaplan-Meier method and compared them using the log-rank test (Mantel-Cox using GraphPad Prism). Several curves proved statistically significant (<i>p</i><0.01) in comparison of each treatment with placebo.</p>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "adefovir", "pmeo-dapym", "mice", "inoculated", "hsv-1"], "article_id"=>755041, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.g008"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_adefovir_and_PMEO_DAPym_on_mortality_in_mice_inoculated_with_HSV_1_or_HSV_2_/755041", "title"=>"Effects of adefovir and PMEO-DAPym on mortality in mice inoculated with HSV-1 or HSV-2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 02:07:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1130966"], "description"=>"<p>Panel <b>A</b>: Production of CC-chemokines by PBMC and the effects of adefovir, tenofovir, and PMEO-DAPym on the expression of the CCR5 receptor. Freshly isolated PBMCs from four healthy donors were incubated for 24 h with medium only (NC) or with adefovir, tenofovir, or PMEO-DAPym. We collected the supernatants and measured the concentrations of MIP-1α (▪), MIP-1β (▴), and RANTES (•) using a Bioplex system (Bio-Rad, Hercules, CA). Shown are means ± SEM. The cells were also collected, and the expression of the CCR5 receptor (□) was measured with flow cytometry using the PE-labeled CCR5 (clone 2D7) mAb; it is shown as percentage of control (± SEM) from four independent representative experiments. Panel <b>B</b>: Chemokine mRNA expression upon PMEO-DAPym exposure to PBMC. RT-PCR analysis of MIP-1α, MIP-1β, RANTES, and GAPDH (control) expression in PBMC treated with 100-µg/ml PMEO-DAPym for 4 h. Similar results were obtained with PBMC from three different donors. Results from one representative donor are shown.</p>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "ccr5", "chemokine", "mrna", "pbmc", "cultures"], "article_id"=>755046, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.g009"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_CC_chemokines_CCR5_and_chemokine_mRNA_expression_in_PBMC_cultures_after_drug_treatment_/755046", "title"=>"Expression of CC-chemokines, CCR5 and chemokine mRNA expression in PBMC cultures after drug treatment.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 02:07:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1130967"], "description"=>"<p>PBMCs were incubated with adefovir, tenofovir, or PMEO-DAPym for 3 days. The mitogenic lectin PHA (at 2 µg/ml) was included as a positive control. We measured cell surface expression of CD4 and the activation markers CD69 (top panel), CD25 (middle panel), and HLA-DR (bottom panel) using flow cytometry with the fluorescein isothiocyanate-labeled CD4-specific mAb (clone SK3) and the phycoerythrin-labeled CD69, CD25, HLA-DR-specific mAbs. Shown are means ± SEM from two independent experiments.</p>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "activation", "markers", "pbmcs", "treated"], "article_id"=>755047, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.g010"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_activation_markers_on_PBMCs_treated_with_adefovir_tenofovir_or_PMEO_DAPym_/755047", "title"=>"Expression of activation markers on PBMCs treated with adefovir, tenofovir, or PMEO-DAPym.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 02:07:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1130968"], "description"=>"<p>We treated PBMC with the drugs for 24 h and collected and analyzed the cells using flow cytometry. Cell surface expression of CD4 and the chemokine receptor CCR5 were measured with the fluorescein isothiocyanate-labeled CD4 specific mAb (clone SK3) and the phycoerythrin-labeled CCR5 (clone 2D7). The percentages of positive cells in each quadrant of the dot plots are given. The data shown are from one representative experiment that was independently repeated at least four times.</p>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "hiv-1", "coreceptor", "ccr5", "pbmcs"], "article_id"=>755048, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.g011"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_the_HIV_1_coreceptor_CCR5_on_PBMCs_after_treatment_with_adefovir_tenofovir_or_PMEO_DAPym_/755048", "title"=>"Expression of the HIV-1 coreceptor CCR5 on PBMCs after treatment with adefovir, tenofovir, or PMEO-DAPym.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 02:07:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1130970"], "description"=>"<p>PBMCs were treated with medium alone or with various concentrations of adefovir, tenofovir, or PMEO-DAPym, and the supernatants were collected after 24 h. Then, freshly isolated PBMCs were incubated at 37°C for 1 h with these various supernatants, with medium alone, or with LD78β (control) at 100 ng/ml, 10 ng/ml, and 1 ng/ml. We measured the expression of the CCR5 receptor using flow cytometry with the phycoerythrin-labeled CCR5 (clone 2D7) mAb: shown are the percentages (means ± SEM for two independent experiments) of CCR5+ cells.</p>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "supernatants", "incubation", "pbmcs", "pmeo-dapym"], "article_id"=>755050, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.g012"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_the_supernatants_collected_after_incubation_of_PBMCs_with_adefovir_tenofovir_and_PMEO_DAPym_on_the_expression_of_CCR5_/755050", "title"=>"Effects of the supernatants collected after incubation of PBMCs with adefovir, tenofovir, and PMEO-DAPym on the expression of CCR5.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-07-25 02:07:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1130971"], "description"=>"a<p>Four separate experiments were carried out in which three non-radiolabeled dNTPs were present at 100 µM and the fourth dNTP was radiolabeled and present at 1 to 3.2 µM depending on the nature of the [<sup>3</sup>H]dNTP. The 50% inhibitory concentration was defined as the drug metabolite concentration required to inhibit HSV DNA polymerase-catalysed DNA synthesis by 50%, using different (radiolabeled) dNTPs as direct competing substrates. As the primer/template, gapped calf thymus DNA was used.</p>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "diphosphate", "metabolites", "pmeo-dapym", "hsv"], "article_id"=>755051, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.t006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibitory_activity_of_the_diphosphate_metabolites_of_adefovir_tenofovir_and_PMEO_DAPym_against_HSV_DNA_/755051", "title"=>"Inhibitory activity of the diphosphate metabolites of adefovir, tenofovir, and PMEO-DAPym against HSV DNA.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-07-25 02:07:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1130972"], "description"=>"<p>Inhibitory activity of PMEO-DAPym and acyclovir against HSV-2 in human lymphoid tissue <i>ex vivo</i>.</p>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "pmeo-dapym", "acyclovir", "hsv-2", "lymphoid"], "article_id"=>755052, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.t004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibitory_activity_of_PMEO_DAPym_and_acyclovir_against_HSV_2_in_human_lymphoid_tissue_ex_vivo_/755052", "title"=>"Inhibitory activity of PMEO-DAPym and acyclovir against HSV-2 in human lymphoid tissue <i>ex vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-07-25 02:07:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1130973"], "description"=>"a<p>50% Inhibitory concentration (drug metabolite concentration required to inhibit HIV-1 RT-catalysed DNA polymerization by 50%), using dATP (3.2 µM) as the competing substrate and poly rU.dA as the primer/template.</p>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "diphosphate", "metabolites", "pmeo-dapym", "hiv-1"], "article_id"=>755053, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.t005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibitory_activity_of_the_diphosphate_metabolites_of_adefovir_tenofovir_and_PMEO_DAPym_against_HIV_1_RT_/755053", "title"=>"Inhibitory activity of the diphosphate metabolites of adefovir, tenofovir, and PMEO-DAPym against HIV-1 RT.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-07-25 02:07:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1130974"], "description"=>"<p>Confluent PHK cell cultures were pretreated with the drugs for different periods. Then, the drugs were carefully removed by several washing steps, after which the cultures were infected with HSV-1 or HSV-2. A control experiment in which the drugs were added to the virus-infected cultures for the entire incubation period before the read-out was also carried out (treatment condition: +2 h to 72 h).</p>a<p>The 50% effective concentration (compound concentration required to inhibit HSV infection by 50%) as determined by scoring cytopathogenicity upon microscopical inspection.</p>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "pre-treatment", "phk", "cultures", "drugs", "herpesvirus"], "article_id"=>755054, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.t002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_pre_treatment_of_PHK_primary_human_keratinocyte_cell_cultures_with_the_drugs_on_herpesvirus_infection_/755054", "title"=>"Effect of pre-treatment of PHK (primary human keratinocyte) cell cultures with the drugs on herpesvirus infection.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-07-25 02:07:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1130975"], "description"=>"<p>Virus production was evaluated on day 6 post infection. Infectious HSV-2 (G) was quantified in the supernatants of drug-treated virus-infected cell cultures by titration in Vero cell cultures using the CPE reduction assay (TCID<sub>50</sub>/ml). The inhibition of viral replication was expressed in percentages and calculated with respect to the virus production in infected untreated macrophages. The inhibition of cytopathicity by the drugs was evaluated from microscopic inspection and was in agreement with the dose-dependent reduction of virus production. The data shown are from one representative experiment that was independently repeated three times.</p>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "pmeo-dapym", "hsv-2", "cultures", "cpe", "assay", "pfu"], "article_id"=>755055, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.t003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibitory_activity_of_tenofovir_adefovir_and_PMEO_DAPym_against_HSV_2_in_primary_M_M_cultures_as_determined_with_the_CPE_reduction_assay_and_the_PFU_reduction_assay_/755055", "title"=>"Inhibitory activity of tenofovir, adefovir, and PMEO-DAPym against HSV-2 in primary M/M cultures as determined with the CPE reduction assay and the PFU reduction assay.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-07-25 02:07:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1130976"], "description"=>"a<p>50% effective concentration (compound concentration required to inhibit virus-induced cytopathicity in cell culture by 50%).</p>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "antiviral", "anp", "derivatives"], "article_id"=>755056, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparative_antiviral_activity_of_ANP_derivatives_in_cell_culture_/755056", "title"=>"Comparative antiviral activity of ANP derivatives in cell culture.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-07-25 02:07:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1130977", "https://ndownloader.figshare.com/files/1130978"], "description"=>"<div><p>Human immunodeficiency virus (HIV) infection is often accompanied by infection with other pathogens, in particular herpes simplex virus type 2 (HSV-2). The resulting coinfection is involved in a vicious circle of mutual facilitations. Therefore, an important task is to develop a compound that is highly potent against both viruses to suppress their transmission and replication. Here, we report on the discovery of such a compound, designated PMEO-DAPym. We compared its properties with those of the structurally related and clinically used acyclic nucleoside phosphonates (ANPs) tenofovir and adefovir. We demonstrated the potent anti-HIV and -HSV activity of this drug in a diverse set of clinically relevant <i>in vitro</i>, <i>ex vivo</i>, and <i>in vivo</i> systems including (i) CD4<sup>+</sup> T-lymphocyte (CEM) cell cultures, (ii) embryonic lung (HEL) cell cultures, (iii) organotypic epithelial raft cultures of primary human keratinocytes (PHKs), (iv) primary human monocyte/macrophage (M/M) cell cultures, (v) human <i>ex vivo</i> lymphoid tissue, and (vi) athymic nude mice. Upon conversion to its diphosphate metabolite, PMEO-DAPym markedly inhibits both HIV-1 reverse transcriptase (RT) and HSV DNA polymerase. However, in striking contrast to tenofovir and adefovir, it also acts as an efficient immunomodulator, inducing β-chemokines in PBMC cultures, in particular the CCR5 agonists MIP-1β, MIP-1α and RANTES but not the CXCR4 agonist SDF-1, without the need to be intracellularly metabolized. Such specific β-chemokine upregulation required new mRNA synthesis. The upregulation of β-chemokines was shown to be associated with a pronounced downmodulation of the HIV-1 coreceptor CCR5 which may result in prevention of HIV entry. PMEO-DAPym belongs conceptually to a new class of efficient multitargeted antivirals for concomitant dual-viral (HSV/HIV) infection therapy through inhibition of virus-specific pathways (i.e. the viral polymerases) and HIV transmission prevention through interference with host pathways (i.e. CCR5 receptor down regulation).</p></div>", "links"=>[], "tags"=>["Drugs and devices", "Drug research and development", "drug discovery", "Infectious diseases", "Viral diseases", "Herpes simplex", "hiv", "multi-targeted", "dual", "anti-hiv", "anti-hsv"], "article_id"=>755057, "categories"=>["Medicine"], "users"=>["Jan Balzarini", "Graciela Andrei", "Emanuela Balestra", "Dana Huskens", "Christophe Vanpouille", "Andrea Introini", "Sonia Zicari", "Sandra Liekens", "Robert Snoeck", "Antonín Holý", "Carlo-Federico Perno", "Leonid Margolis", "Dominique Schols"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1003456.s001", "https://dx.doi.org/10.1371/journal.ppat.1003456.s002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_A_Multi_targeted_Drug_Candidate_with_Dual_Anti_HIV_and_Anti_HSV_Activity_/755057", "title"=>"A Multi-targeted Drug Candidate with Dual Anti-HIV and Anti-HSV Activity", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-07-25 02:07:19"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"8", "full-text"=>"11", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"10"}
  • {"unique-ip"=>"7", "full-text"=>"6", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"11"}
  • {"unique-ip"=>"7", "full-text"=>"7", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"12"}
  • {"unique-ip"=>"4", "full-text"=>"5", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
  • {"unique-ip"=>"6", "full-text"=>"6", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"8", "full-text"=>"19", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
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  • {"unique-ip"=>"3", "full-text"=>"2", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}
  • {"unique-ip"=>"56", "full-text"=>"104", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"24", "supp-data"=>"2", "cited-by"=>"1", "year"=>"2019", "month"=>"9"}
  • {"unique-ip"=>"9", "full-text"=>"10", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"10"}
  • {"unique-ip"=>"11", "full-text"=>"6", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2019", "month"=>"12"}

Relative Metric

{"start_date"=>"2013-01-01T00:00:00Z", "end_date"=>"2013-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences", "average_usage"=>[269, 466, 588, 697, 800, 896, 988, 1076, 1165, 1254, 1340, 1417]}, {"subject_area"=>"/Biology and life sciences/Biochemistry", "average_usage"=>[266, 468, 593, 703, 804, 903, 993, 1084, 1171, 1256, 1339, 1422, 1492]}, {"subject_area"=>"/Biology and life sciences/Cell biology", "average_usage"=>[272, 472, 600, 713, 815, 911, 1004, 1094, 1185, 1273, 1358, 1441]}, {"subject_area"=>"/Biology and life sciences/Microbiology", "average_usage"=>[293, 503, 638, 755, 861, 960, 1056, 1146, 1239, 1323, 1403, 1491, 1568]}, {"subject_area"=>"/Biology and life sciences/Organisms", "average_usage"=>[281, 484, 611, 728, 835, 934, 1030, 1123, 1214, 1299, 1383, 1464]}, {"subject_area"=>"/Medicine and health sciences", "average_usage"=>[264, 460, 584, 692, 794, 887, 978, 1067, 1154, 1241, 1328, 1408, 1474]}, {"subject_area"=>"/Medicine and health sciences/Immunology", "average_usage"=>[262, 463, 587, 693, 790, 882, 965, 1051, 1135, 1218, 1300, 1376, 1438]}, {"subject_area"=>"/Medicine and health sciences/Pathology and laboratory medicine", "average_usage"=>[267, 466, 592, 709, 806, 901, 989, 1075, 1162, 1254, 1342, 1424, 1486]}]}
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