title: Synergistic suppression of dengue virus replication using a combination of nucleoside analogs and nucleoside synthesis inhibitors.
abstract: Dengue virus (DENV) is the most prevalent mosquito-borne viral pathogen in humans. Currently, there is no clinically approved vaccine or antiviral for DENV. Combination therapy is a common practice in antiviral treatment and a potential approach to search for new treatments for infectious pathogens. In this study, we performed a combination treatment in cell culture by using three distinct classes of inhibitors, including ribavirin (a guanosine analog with several antiviral mechanisms), brequinar (a pyrimidine biosynthesis inhibitor), and INX-08189 (a guanosine analog). The compound pairs were evaluated for antiviral activity by use of a DENV-2 luciferase replicon assay. Our result indicated that the combination of ribavirin and INX-08189 exhibited strong antiviral synergy. This result suggests that synergy can be achieved with compound pairs in which one compound suppresses the synthesis of the nucleoside for which the other compound is a corresponding nucleoside analog. In addition, we found that treatment of cells with brequinar alone could activate interferon-stimulated response elements (ISREs); furthermore, brequinar and NITD-982 (another pyrimidine biosynthesis inhibitor) potentiated interferon-induced ISRE activation. Compared to treatment with brequinar, treatment of cells with ribavirin alone could also induce ISRE activation, but to a lesser extent; however, when cells were cotreated with ribavirin and beta interferon, ribavirin did not augment the interferon-induced ISRE activation.
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Kim Long
authors.initials: KL
authors.lastname: Yeo
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Yen-Liang
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Hao Ying
authors.initials: HY
authors.lastname: Xu
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Hongping
authors.initials: H
authors.lastname: Dong
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Qing-Yin
authors.initials: QY
authors.lastname: Wang
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Yokokawa
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore pei_yong.shi@novartis.com yen_liang.chen@novartis.com.
authors.forename: Pei-Yong
authors.initials: PY
authors.lastname: Shi
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003716:Dengue Virus / Q000187:drug effects*; D004338:Drug Combinations; D004357:Drug Synergism; D057809:HEK293 Cells; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology; D016899:Interferon-beta / Q000494:pharmacology; D009705:Nucleosides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000494:pharmacology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D012254:Ribavirin / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D004338:Drug Combinations; D007369:Interferon Inducers; D009705:Nucleosides; D012254:Ribavirin; D016899:Interferon-beta; D010088:Oxidoreductases; C019999:dehydroorotate dehydrogenase