Hwang Der-Ren, Lin Ren-Kuo, Leu Guang-Zhou, Lin Tiao-Yin, Lien Tzu-Wen, Yu Ming-Chen, Yeh Chau-Ting, Hsu John T-A
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan, Republic of China.
Antimicrob Agents Chemother. 2005 Oct;49(10):4197-202. doi: 10.1128/AAC.49.10.4197-4202.2005.
Chronic hepatitis C virus (HCV) infection is a worldwide health problem causing serious complications, such as liver cirrhosis and hepatoma. Alpha interferon (IFN-alpha) or its polyethylene glycol-modified form combined with ribavirin is the only recommended therapy. However, an alternative therapy is needed due to the unsatisfactory cure rate of the IFN-based therapy. Using a modified reporter assay based on the HCV subgenomic-replicon system, we found that sodium stibogluconate (SSG), a compound used for leishmania treatment, suppressed HCV replication. We have previously reported that SSG is effective at inhibiting HCV replication in a cell line permissive for HCV infection/replication and in an ex vivo assay using fresh human liver slices obtained from patients infected with HCV (26). In this study, we show that the SSG 50% inhibitory dose for HCV replication is 0.2 to 0.3 mg/ml (equivalent to 345 to 517 microM of Sb) in the HCV subgenomic-replicon system. We also found that SSG and IFN-alpha exert a strong synergistic anti-HCV effect in both the traditional isobologram analysis and the median effect principle (CalcuSyn analysis). The combination of SSG and IFN-alpha could sustain the antiviral response better than SSG or IFN-alpha alone. The results suggest that SSG may be a good drug candidate for use in combination with other therapeutics, such as IFN-alpha and ribavirin, to treat HCV infection.
慢性丙型肝炎病毒（HCV）感染是一个全球性的健康问题，会引发严重并发症，如肝硬化和肝癌。α干扰素（IFN-α）或其聚乙二醇修饰形式与利巴韦林联合使用是唯一推荐的治疗方法。然而，由于基于干扰素的治疗治愈率不尽人意，需要一种替代疗法。通过基于HCV亚基因组复制子系统的改良报告基因检测，我们发现用于治疗利什曼病的化合物葡萄糖酸锑钠（SSG）可抑制HCV复制。我们之前报道过，SSG在允许HCV感染/复制的细胞系以及使用从HCV感染患者获取的新鲜人肝切片进行的体外检测中，对抑制HCV复制有效（26）。在本研究中，我们表明在HCV亚基因组复制子系统中，SSG对HCV复制的50%抑制剂量为0.2至0.3毫克/毫升（相当于345至517微摩尔的锑）。我们还发现，在传统的等效线图分析和中位效应原理（CalcuSyn分析）中，SSG和IFN-α均发挥强大的协同抗HCV作用。SSG与IFN-α联合使用比单独使用SSG或IFN-α能更好地维持抗病毒反应。结果表明，SSG可能是与其他疗法（如IFN-α和利巴韦林）联合用于治疗HCV感染的良好候选药物。
