ME3738 enhances the effect of interferon and inhibits hepatitis C virus replication both in vitro and in vivo

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• 作者：Hiromi Abe¹ ; ³ ; Michio Imamura¹ ; ² ; Nobuhiko Hiraga¹ ; ² ; Masataka Tsuge¹ ; ² ; Fukiko Mitsui¹ ; ² ; Tomokazu Kawaoka¹ ; ² ; Shoichi Takahashi¹ ; ² ; Hidenori Ochi² ; ³ ; Toshiro Maekawa³ ; C. Nelson Hayes¹ ; ³ ; Chise Tateno² ; ⁴ ; Katsutoshi Yoshizato² ; ⁴ ; Shoichi Murakami⁵ ; Nobuyuki Yamashita⁵ ; Takashi Matsuhira⁵ ; Kenji Asai⁵ ; Kazuaki Chayama¹ ; ² ; ³ ; ^{chayama@hiroshima-u.ac.jp"" rel=""nofollow}
• 关键词：Human hepatocyte chimeric mouse ; Interferon-stimulated genes
• 刊名：Journal of Hepatology
• 出版年：2011
• 出版时间：July 2011
• 年：2011
• 卷：55
• 期：1
• 页码：11-18
• 全文大小：1096 K

文摘

Background & Aims

ME3738 (22β-methoxyolean-12-ene-3β, 24-diol), a derivative of soyasapogenol B, attenuates liver disease in several animal models of acute and chronic liver injury. ME3738 is thought to inhibit replication of hepatitis C virus (HCV) by enhancing interferon (IFN)-β production, as determined using the HCV full-length binary expression system. We examined the effect of ME3738 combined with IFN-α on HCV replication using the genotype 1b subgenomic replicon system and an in vivo mouse HCV model.

Methods

HCV replicon cells (ORN/3-5B/KE cells and Con1 cells) were incubated with ME3738 and/or IFN-α, and then intracellular IFN-stimulated genes (ISGs) and HCV RNA replication were analyzed by reverse-transcription-real time polymerase chain reaction and luciferase reporter assay. HCV-infected human hepatocyte chimeric mice were also treated with ME3738 and/or IFN-α for 4 weeks. Mouse serum HCV RNA titer, HCV core antigen, and ISGs expression in the liver were measured.

Results

ME3738 induced gene expression of oligoadenylate synthetase 1 and inhibited HCV replication in both HCV replicon cells. The drug enhanced the effect of IFN to significantly increase ISG expression levels, inhibit HCV replication in replicon cells, and reduce mouse serum HCV RNA and core antigen levels in mouse livers. The combination treatment was not hepatotoxic as evident histologically and did not reduce human serum albumin in mice.

Conclusions

ME3738 inhibited HCV replication, enhancing the effect of IFN-α to increase ISG expression both in vitro and in vivo, suggesting that the combination of ME3738 and IFN might be useful therapeutically for patients with chronic hepatitis C.