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Synergistic suppression of dengue virus replication using a combination of nucleoside analogs and nucleoside synthesis inhibitors

Yeo, Kim Long and Chen, Yen Liang and Xu, Haoying and Dong, Hongping and Wang, Qingyin and Yokokawa, Fumiaki and Shi, Pei-Yong (2015) Synergistic suppression of dengue virus replication using a combination of nucleoside analogs and nucleoside synthesis inhibitors. Antimicrobial Agents and Chemotherapy, 59 (4). pp. 2086-2093.

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 treatment for infectious pathogens. In this study, we performed a combination treatment in cell culture 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 their antiviral activities using a DENV-2 luciferase replicon assay. Our result indicated combination of Ribavirin + 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 element (ISRE); furthermore, brequinar and NITD-982 (another pyrimidine biosynthesis inhibitor) can potentiate the interferon-induced ISRE activation. Compared with brequinar, treatment of cells with ribavirin alone could also induce ISRE activation, but to a less extend; however, when cells were co-treated with ribavirin and interferon-β, ribavirin did not augment the interferon-induced ISRE activation.

Item Type: Article
Keywords: Dengue, antiviral, synergy, ribavirin, brequinar, IMPDH, DHODH
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/23128

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