Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore.
Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore.
Antiviral Res. 2019 Nov;171:104589. doi: 10.1016/j.antiviral.2019.104589. Epub 2019 Aug 14.
Dengue virus, the causative agent for the dengue fever, infects approximately 50-100 million people worldwide per year. The high incidence of dengue fever, along with its potential to develop into a severe, life-threatening form, resulted in great interest in the discovery of an antiviral against it. In this study, we constructed a DENV2-EGFP infectious clone, established a fluorescence-based, high-throughput screening platform, and conducted a screen for anti-DENV compounds on a flavonoid-derivative library, Amongst the hits identified, ST081006 was found to be a strong inhibitor of the DENV replication. Time-course studies suggest that the presence of ST081006 is necessary to inhibit successive rounds of virus replication. Further investigations demonstrated that ST081006 affects the synthesis of both viral protein and viral RNA, and one anti-DENV mechanism is the direct inhibition of viral protein synthesis. The replication of all dengue serotypes, along with that of the enterovirus EV-A71, was shown to be affected by ST081006. Attempts to generate ST081006-resistant DENV were unsuccessful, and thus hints at host factors as potential drug target. Together, these results suggest that ST081006 affect DENV replication, likely by acting on a target involved in the viral protein and/or RNA synthesis pathway.
登革热病毒是登革热的病原体，每年在全球感染约 5000 万至 1 亿人。登革热的高发病率及其可能发展为严重的、危及生命的形式，导致人们对发现抗登革热病毒的药物产生了极大的兴趣。在本研究中，我们构建了 DENV2-EGFP 感染性克隆，建立了基于荧光的高通量筛选平台，并对黄酮类衍生物文库进行了抗 DENV 化合物筛选。在鉴定的命中化合物中，ST081006 被发现是一种强烈抑制 DENV 复制的物质。时程研究表明，ST081006 的存在对于抑制连续轮次的病毒复制是必需的。进一步的研究表明，ST081006 影响病毒蛋白和病毒 RNA 的合成，一种抗 DENV 的机制是直接抑制病毒蛋白的合成。ST081006 影响所有登革热血清型以及肠道病毒 EV-A71 的复制。尝试生成 ST081006 抗性 DENV 是不成功的，因此提示宿主因素可能是潜在的药物靶点。总之，这些结果表明 ST081006 影响 DENV 复制，可能通过作用于涉及病毒蛋白和/或 RNA 合成途径的靶标。
