期刊
ANTIVIRAL RESEARCH
卷 115, 期 -, 页码 94-104出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.antiviral.2014.12.017
关键词
HCV; Viral entry; SKI-1/S1P; PF-429242; SREBP; LDLR
资金
- Canadian Institutes of Health Research (CIHR) [MOP 93792]
- Le Fonds de recherche du Quebec (FRSQ)
- La fondation Universitaire Armand-Frappier
- CIHR [MOP 93792]
- Canada Research Chair [216684]
- Agence nationale de recherches sur le sida et les hepatites virales
Worldwide, approximately 170 million individuals are afflicted with chronic hepatitis C virus (HCV) infection. To prevent the development of inherent diseases such as cirrhosis and hepatocellular carcinoma, tremendous efforts have been made, leading to the development of promising new treatments. However, their efficiency is still dependent on the viral genotype. Additionally, these treatments that target the virus directly can trigger the emergence of resistant variants. In a previous study, we have demonstrated that a long-term (72 h) inhibition of SKI-1/S1P, a master lipogenic pathway regulator through activation of SREBP, resulted in impaired HCV genome replication and infectious virion secretion. In the present study, we sought to investigate the antiviral effect of the SKI-1/S1P small molecule inhibitor PF-429242 at the early steps of the HCV lifecycle. Our results indicate a very potent antiviral effect of the inhibitor early in the viral lifecycle and that the overall action of the compound relies on two different contributions. The first one is SREBP/SKI-1/S1P dependent and involves LDLR and NPC1L1 proteins, while the second one is SREBP independent. Overall, our study confirms that SKI-1/S1P is a relevant target to impair HCV infection and that PF-429242 could be a promising candidate in the field of HCV infection treatment. (C) 2015 Elsevier B.V. All rights reserved.
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