title: Novel antiviral activity of bromocriptine against dengue virus replication.
abstract: Dengue virus (DENV) infectious disease is a major public health problem worldwide; however, licensed vaccines or specific antiviral drugs against this infection are not available. To identify novel anti-DENV compounds, we screened 1280 pharmacologically active compounds using focus reduction assay. Bromocriptine (BRC) was found to have potent anti-DENV activity and low cytotoxicity (half maximal effective concentration [EC50], 0.8-1.6 μM; and half maximal cytotoxicity concentration [CC50], 53.6 μM). Time-of-drug-addition and time-of-drug-elimination assays suggested that BRC inhibits translation and/or replication steps in the DENV life cycle. A subgenomic replicon system was used to verify that BRC restricts RNA replication step. Furthermore, a single amino acid substitution (N374H) was detected in the NS3 protein that conferred resistance to BRC. In summary, BRC was found to be a novel DENV inhibitor and a potential candidate for the treatment of DENV infectious disease.
authors.affiliation: Laboratory of Primate Model, Institute for Virus Research, Kyoto University, Kyoto, Japan; Department of Virology 1, National Institute of Infectious Diseases, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Kato
authors.affiliation: Laboratory of Primate Model, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ishida
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Satoru
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Subhash G
authors.initials: SG
authors.lastname: Vasudevan
authors.affiliation: Department of Virology 1, National Institute of Infectious Diseases, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tajima
authors.affiliation: Department of Virology 1, National Institute of Infectious Diseases, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Takasaki
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Youichi
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Koji
authors.initials: K
authors.lastname: Ichiyama
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Laboratry of Public Health, Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yoshii
authors.affiliation: Laboratry of Public Health, Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Takashima
authors.affiliation: Laboratory of Primate Model, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Laboratory of Primate Model, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Miura
authors.affiliation: Laboratory of Primate Model, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Igarashi
authors.affiliation: Laboratory of Primate Model, Institute for Virus Research, Kyoto University, Kyoto, Japan; Viral Infectious Diseases Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan. Electronic address: hishiki-tk@igakuken.or.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hishiki
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001971:Bromocriptine / Q000494:pharmacology*; D003715:Dengue / Q000188:drug therapy; D003716:Dengue Virus / Q000187:drug effects* / Q000502:physiology; D024882:Drug Resistance, Viral; D006801:Humans; D012093:Replicon / Q000187:drug effects; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D001971:Bromocriptine
keywords: Antiviral drug; Bromocriptine; Dengue virus; Focus assay; Replicon; Time-of-drug addition