title: Antiviral activity of an N-allyl acridone against dengue virus.
abstract: BACKGROUND
  Dengue virus (DENV), a member of the family Flaviviridae, is at present the most widespread causative agent of a human viral disease transmitted by mosquitoes. Despite the increasing incidence of this pathogen, there are no antiviral drugs or vaccines currently available for treatment or prevention. In a previous screening assay, we identified a group of N-allyl acridones as effective virus inhibitors. Here, the antiviral activity and mode of action targeted to viral RNA replication of one of the most active DENV-2 inhibitors was further characterized.
  
  
  RESULTS
  The compound 10-allyl-7-chloro-9(10H)-acridone, designated 3b, was active to inhibit the in vitro infection of Vero cells with the four DENV serotypes, with effective concentration 50% (EC50) values in the range 12.5-27.1 μM, as determined by virus yield inhibition assays. The compound was also effective in human HeLa cells. No cytotoxicity was detected at 3b concentrations up to 1000 μM. Mechanistic studies demonstrated that virus entry into the host cell was not affected, whereas viral RNA synthesis was strongly inhibited, as quantified by real time RT-PCR. The addition of exogenous guanosine together with 3b rescued only partially the infectivity of DENV-2.
  
  
  CONCLUSIONS
  The acridone derivative 3b selectively inhibits the infection of Vero cells with the four DENV serotypes without a direct interaction with the host cell or the virion but interfering specifically with the intracellular virus multiplication. The mode of antiviral action for this acridone apparently involves the cellular enzyme inosine-monophospahe dehydrogenase together with another still unidentified target related to DENV RNA synthesis.
authors.affiliation: Laboratorio de Virología, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, UBA, Ciudad Universitaria, Piso 4, Buenos Aires, Pabellón, 1428, Argentina. m.bmazzucco@yahoo.com.ar.|Present address: Laboratorio de Reproducción y Metabolismo, Facultad de Medicina, CEFYBO-CONICET, UBA, Buenos Aires, 1121, Argentina. m.bmazzucco@yahoo.com.ar.
authors.forename: María B
authors.initials: MB
authors.lastname: Mazzucco
authors.affiliation: Laboratorio de Virología, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, UBA, Ciudad Universitaria, Piso 4, Buenos Aires, Pabellón, 1428, Argentina. ltalarico@infant.org.ar.|Present address: Fundación Infant, Buenos Aires, 1406, Argentina. ltalarico@infant.org.ar.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Talarico
authors.affiliation: Graduate School of Science and Engineering, Koc University, Rumelifener yolu, Istanbul, Sarıyer, 34450, Turke. svatansever13@ku.edu.tr.
authors.forename: Sezen
authors.initials: S
authors.lastname: Vatansever
authors.affiliation: Laboratorio de Virología, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, UBA, Ciudad Universitaria, Piso 4, Buenos Aires, Pabellón, 1428, Argentina. anacarro@qb.fcen.uba.ar.|IQUIBICEN-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina. anacarro@qb.fcen.uba.ar.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Carro
authors.affiliation: CIHIDECAR (CONICET), Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, UBA, Ciudad Universitaria, Pabellón 2, Piso 3, Buenos Aires, 1428, Argentina. mfascio@qo.fcen.uba.ar.
authors.forename: Mirta L
authors.initials: ML
authors.lastname: Fascio
authors.affiliation: CIHIDECAR (CONICET), Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, UBA, Ciudad Universitaria, Pabellón 2, Piso 3, Buenos Aires, 1428, Argentina. norma@qo.fcen.uba.ar.
authors.forename: Norma B
authors.initials: NB
authors.lastname: D'Accorso
authors.affiliation: Laboratorio de Virología, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, UBA, Ciudad Universitaria, Piso 4, Buenos Aires, Pabellón, 1428, Argentina. cygarcia@qb.fcen.uba.ar.|IQUIBICEN-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina. cygarcia@qb.fcen.uba.ar.
authors.forename: Cybele C
authors.initials: CC
authors.lastname: García
authors.affiliation: Laboratorio de Virología, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, UBA, Ciudad Universitaria, Piso 4, Buenos Aires, Pabellón, 1428, Argentina. edamonte@qb.fcen.uba.ar.|IQUIBICEN-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina. edamonte@qb.fcen.uba.ar.
authors.forename: Elsa B
authors.initials: EB
authors.lastname: Damonte
mesh_terms: D054831:Acridones / Q000494:pharmacology*; D000498:Allyl Compounds / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D003716:Dengue Virus / Q000187:drug effects*; D012367:RNA, Viral / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D054831:Acridones; D000498:Allyl Compounds; D000998:Antiviral Agents; D012367:RNA, Viral