Antiviral candidates against the hepatitis E virus (HEV) and their combinations inhibit HEV growth in in vitro
Antiviral candidates against the hepatitis E virus (HEV) and their combinations inhibit HEV growth in in vitro
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DOI：
10.1016/j.antiviral.2019.104570
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发表时间：
2019-10-01
影响因子：
7.6
通讯作者：
Okamoto, Hiroaki
中科院分区：
文献类型：
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作者：
Nishiyama, Takashi;Kobayashi, Tominari;Okamoto, Hiroaki
戊型肝炎是一个全球性的公共卫生问题。利巴韦林（RBV）和聚乙二醇干扰素α目前用于治疗戊型肝炎。最近，索非布韦（SOF），一种抗丙型肝炎病毒的核苷酸类似物，也与RBV联合用于慢性戊型肝炎患者。然而，这种组合疗法有时不能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，用于体外筛选含有Gaussia荧光素酶报告基因的基因型3 HEV株。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）抑制报告基因组的复制，而只有RBV、SOF、2CMC和2CMG抑制基因型3 HEV在培养细胞中的生长。在报告试验中，2CMG与RBV（2CMG/RBV）表现出协同作用，SOF/RBV和2CMC/RBV表现出拮抗作用，但这三种核苷类似物与RBV在抑制培养细胞中HEV生长方面具有相加作用。此外，SOF和2CMG，与四种干扰素（IFN-α 2b，IFN-λ 1，IFN-λ 2和IFN-λ 3），有效地抑制HEV的生长和清除培养细胞中的HEV。这些结果表明，与RBV或干扰素组合，SOF和2CMG将是开发抗HEV核苷（酸）类似物的有希望的碱基。
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-alpha 2b, IFN-lambda 1, IFN-lambda 2 and IFN-lambda 3), 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.