Vaccine and Infectious Disease Research Center, Translational Health Science and Technology Institute, Faridabad, India.
Shiv Nadar University, Gautam Buddha Nagar, Uttar Pradesh, India.
Sci Rep. 2017 Jul 19;7(1):5816. doi: 10.1038/s41598-017-04449-3.
Hepatitis C virus (HCV) is a global pathogen and infects more than 185 million individuals worldwide. Although recent development of direct acting antivirals (DAA) has shown promise in HCV therapy, there is an urgent need for the development of more affordable treatment options. We initiated this study to identify novel inhibitors of HCV through screening of compounds from the National Cancer Institute (NCI) diversity dataset. Using cell-based assays, we identified NSC-320218 as a potent inhibitor against HCV with an EC of 2.5 μM and CC of 75 μM. The compound inhibited RNA dependent RNA polymerase (RdRp) activity of all six major HCV genotypes indicating a pan-genotypic effect. Limited structure-function analysis suggested that the entire molecule is necessary for the observed antiviral activity. However, the compound failed to inhibit HCV NS5B activity in vitro, suggesting that it may not be directly acting on the NS5B protein but could be interacting with a host protein. Importantly, the antiviral compound also inhibited dengue virus and hepatitis E virus replication in hepatocytes. Thus, our study has identified a broad-spectrum antiviral therapeutic agent against multiple viral infections.
丙型肝炎病毒 (HCV) 是一种全球性病原体，感染了全球超过 1.85 亿人。尽管直接作用抗病毒药物 (DAA) 的最新发展在 HCV 治疗中显示出了希望，但仍迫切需要开发更经济实惠的治疗方案。我们通过筛选国立癌症研究所 (NCI) 多样性数据集的化合物，启动了这项研究以寻找 HCV 的新型抑制剂。通过细胞测定，我们发现 NSC-320218 是一种有效的 HCV 抑制剂，其 EC50 为 2.5 μM，CC50 为 75 μM。该化合物抑制了所有六种主要 HCV 基因型的 RNA 依赖性 RNA 聚合酶 (RdRp) 活性，表明具有泛基因型作用。有限的结构功能分析表明，整个分子对于观察到的抗病毒活性是必需的。然而，该化合物未能抑制 HCV NS5B 的体外活性，表明它可能不是直接作用于 NS5B 蛋白，而是可能与宿主蛋白相互作用。重要的是，该抗病毒化合物还抑制了肝细胞中的登革热病毒和戊型肝炎病毒复制。因此，我们的研究鉴定了一种针对多种病毒感染的广谱抗病毒治疗剂。
