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Structure-activity relationships of fluorene compounds inhibiting HCV variants.
Antiviral Research ( IF 4.5 ) Pub Date : 2019-12-17 , DOI: 10.1016/j.antiviral.2019.104678
Hee Sun Kim 1 , Youngsu You 2 , Jaegon Mun 3 , Changdev G Gadhe 4 , Heejo Moon 2 , Jae Seung Lee 1 , Ae Nim Pae 4 , Michinori Kohara 5 , Gyochang Keum 4 , Byeong Moon Kim 2 , Sung Key Jang 6
Affiliation  

Approximately 71 million people suffer from hepatitis C virus (HCV) infection worldwide. Persistent HCV infection causes liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma, resulting in approximately 400,000 deaths annually. Effective direct-acting antiviral agents (DAAs) have been developed and are currently used for HCV treatment targeting the following three proteins: NS3/4A proteinase that cleaves the HCV polyprotein into various functional proteins, RNA-dependent RNA polymerase (designated as NS5B), and NS5A, which is required for the formation of double membrane vesicles serving as RNA replication organelles. At least one compound inhibiting NS5A is included in current HCV treatment regimens due to the high efficacy and low toxicity of drugs targeting NS5A. Here we report fluorene compounds showing strong inhibitory effects on GT 1b and 3a of HCV. Moreover, some compounds were effective against resistance-associated variants to DAAs. The structure-activity relationships of the compounds were analyzed. Furthermore, we investigated the molecular bases of the inhibitory activities of some compounds by the molecular docking method.

中文翻译:

抑制HCV变体的芴化合物的构效关系。

全世界约有 7100 万人患有丙型肝炎病毒 (HCV) 感染。持续的 HCV 感染会导致慢性肝炎、肝硬化和肝细胞癌等肝脏疾病,每年导致约 400,000 人死亡。已开发出有效的直接作用抗病毒剂 (DAA),目前用于针对以下三种蛋白质的 HCV 治疗:将 HCV 多蛋白切割成各种功能性蛋白质的 NS3/4A 蛋白酶、RNA 依赖性 RNA 聚合酶(称为 NS5B)、和 NS5A,这是形成作为 RNA 复制细胞器的双膜囊泡所必需的。由于靶向 NS5A 的药物的高效性和低毒性,目前的 HCV 治疗方案中包括至少一种抑制 NS5A 的化合物。在这里,我们报告了对 HCV 的 GT 1b 和 3a 具有强烈抑制作用的芴化合物。此外,一些化合物对抗性相关的 DAA 变体有效。分析了化合物的构效关系。此外,我们通过分子对接方法研究了一些化合物抑制活性的分子基础。
更新日期:2019-12-18
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