Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke-Shi, Tochigi, 329-0498, Japan.
Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke-Shi, Tochigi, 329-0498, Japan; Division of Pathology, Department of Basic Veterinary Medicine, Inner Mongolia Agricultural University College of Veterinary Medicine, Hohhot, Inner Mongolia, China.
Antiviral Res. 2019 Oct;170:104570. doi: 10.1016/j.antiviral.2019.104570. Epub 2019 Jul 27.
Hepatitis E is a global public health problem. Ribavirin (RBV) and pegylated interferon alpha are currently administered to cure hepatitis E. Recently, in combination with RBV, sofosbuvir (SOF), an anti-hepatitis C virus nucleotide analog, is also given to patients with chronic hepatitis E. However, this combinatorial therapy sometimes fails to achieve a sustained virological response. In this study, we used 27 antiviral compounds, including 15 nucleos(t)ide analogs, for in vitro screening against a genotype 3 HEV strain containing a Gaussia luciferase reporter. RBV, SOF, 2'-C-methyladenosine, 2'-C-methylcytidine (2CMC), 2'-C-methylguanosine (2CMG), and two 4'-azido nucleoside analogs (R-1479 and RO-9187) suppressed replication of the reporter genome, while only RBV, SOF, 2CMC and 2CMG inhibited the growth of genotype 3 HEV in cultured cells. Although 2CMG and RBV (2CMG/RBV) exhibited a synergistic effect while SOF/RBV and 2CMC/RBV showed antagonistic effects on the reporter assay, these three nucleos(t)ide analogs acted additively with RBV in inhibiting HEV growth in cultured cells. Furthermore, SOF and 2CMG, with four interferons (IFN-α2b, IFN-λ1, IFN-λ2 and IFN-λ3), inhibited HEV growth efficiently and cleared HEV in cultured cells. These results suggest that, in combination with RBV or interferons, SOF and 2CMG would be promising bases for developing anti-HEV nucleos(t)ide analogs.
戊型肝炎是一个全球性的公共卫生问题。目前，利巴韦林（RBV）和聚乙二醇干扰素α用于治疗戊型肝炎。最近，在与 RBV 联合使用的情况下，索非布韦（SOF），一种抗丙型肝炎病毒核苷酸类似物，也被用于慢性戊型肝炎患者。然而，这种联合治疗有时无法实现持续的病毒学应答。在这项研究中，我们使用了 27 种抗病毒化合物，包括 15 种核苷（酸）类似物，对含有 Gaussia 荧光素酶报告基因的基因型 3 HEV 株进行体外筛选。RBV、SOF、2'-C-甲基腺苷、2'-C-甲基胞苷（2CMC）、2'-C-甲基鸟苷（2CMG）和两种 4'-叠氮核苷类似物（R-1479 和 RO-9187）抑制了报告基因的复制，而只有 RBV、SOF、2CMC 和 2CMG 抑制了培养细胞中基因型 3 HEV 的生长。虽然 2CMG 和 RBV（2CMG/RBV）在报告基因测定中表现出协同作用，而 SOF/RBV 和 2CMC/RBV 表现出拮抗作用，但这三种核苷（酸）类似物在抑制培养细胞中的 HEV 生长方面与 RBV 呈相加作用。此外，SOF 和 2CMG 与四种干扰素（IFN-α2b、IFN-λ1、IFN-λ2 和 IFN-λ3）联合有效地抑制了 HEV 的生长并清除了培养细胞中的 HEV。这些结果表明，SOF 和 2CMG 与 RBV 或干扰素联合使用可能成为开发抗 HEV 核苷（酸）类似物的有前途的基础。
