Up-regulation of glycolipid transfer protein by bicyclol causes spontaneous restriction of hepatitis C virus replication.

Meng-hao Huang; Hu LI; Rong Xue; Jianrui LI; Lihua Wang; Junjun Cheng; Zhouyi WU; Wenjing LI; Jinhua Chen; Xiaoqin LV; Qiang LI; Pei Lan; Limin Zhao; Yongfeng Yang; Zonggen Peng; Jiandong Jiang

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Up-regulation of glycolipid transfer protein by bicyclol causes spontaneous restriction of hepatitis C virus replication.

Author: Meng-Hao HUANG ¹ ; Hu LI ¹ ; Rong XUE ² ; Jianrui LI ¹ ; Lihua WANG ² ; Junjun CHENG ¹ ; Zhouyi WU ¹ ; Wenjing LI ¹ ; Jinhua CHEN ¹ ; Xiaoqin LV ¹ ; Qiang LI ³ ; Pei LAN ³ ; Limin ZHAO ³ ; Yongfeng YANG ² ; Zonggen PENG ¹ ; Jiandong JIANG ¹
Author Information

1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
2. Department of Liver Diseases, the Second Hospital of Nanjing, Southeast University, Nanjing 210003, China.
3. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Publication Type:Journal Article
Keywords: Bicyclol; Glycolipid transfer protein; Hepatitis C virus; Host restrictive factor; Protein interaction
From: Acta Pharmaceutica Sinica B 2019;9(4):769-781
CountryChina
Language:English
Abstract: Bicyclol is a synthetic drug for hepatoprotection in clinic since 2004. Preliminary clinical observations suggest that bicyclol might be active against hepatitis C virus (HCV) with unknown mechanism. Here, we showed that bicyclol significantly inhibited HCV replication and in hepatitis C patients. Using bicyclol as a probe, we identified glycolipid transfer protein (GLTP) to be a novel restrictive factor for HCV replication. The GLTP preferentially bound host vesicle-associated membrane protein-associated protein-A (VAP-A) in competition with the HCV NS5A, causing an interruption of the complex formation between VAP-A and HCV NS5A. As the formation of VAP-A/NS5A complex is essential for viral RNA replication, up-regulation of GLTP by bicyclol reduced the level of VAP-A/NS5A complex and thus inhibited HCV replication. Bicyclol also exhibited an inhibition on HCV variants resistant to direct-acting antiviral agents (DAAs) with an efficacy identical to that on wild type HCV. In combination with bicyclol, DAAs inhibited HCV replication in a synergistic fashion. GLTP appears to be a newly discovered host restrictive factor for HCV replication, Up-regulation of GLTP causes spontaneous restriction of HCV replication.