Abstract
NS2 protein is essential for hepatitis C virus (HCV) replication. NS2 protein was expressed and purified. Aptamers against NS2 protein were raised and antiviral effects of the aptamers were examined. The molecular mechanism through which the aptamers exert their anti-HCV activity was investigated. The data showed that aptamer NS2-3 inhibited HCV RNA replication in replicon cell line and infectious HCV cell culture system. NS2-3 and another aptamer NS2-2 were demonstrated to inhibit infectious virus production without cytotoxicity in vitro. They did not affect hepatitis B virus replication. Interferon beta (IFN-β) and interferon-stimulated genes (ISGs) were not induced by the aptamers in HCV-infected hepatocytes. Furthermore, our study showed that N-terminal region of NS2 protein is involved in the inhibition of HCV infection by NS2-2. I861T within NS2 is the major resistance mutation identified. Aptamer NS2-2 disrupts the interaction of NS2 with NS5A protein. The data suggest that NS2-2 aptamer against NS2 protein exerts its antiviral effects through binding to the N-terminal of NS2 and disrupting the interaction of NS2 with NS5A protein. NS2-specific aptamer is the first NS2 inhibitor and can be used to understand the mechanisms of virus replication and assembly. It may be served as attractive candidates for inclusion in the future HCV direct-acting antiviral combination therapies.
Highlights
Hepatitis C virus (HCV) infects approximately 3% of the world population, leading to chronic hepatitis, liver cirrhosis and even hepatocellular carcinoma [1]
Almost half of the individuals infected with HCV genotype 1 do not response to the current pegylated IFN-a-based therapy
The protease inhibitors against NS34A have been recently approved for the treatment of chronic hepatitis C patients [24]
Summary
Hepatitis C virus (HCV) infects approximately 3% of the world population, leading to chronic hepatitis, liver cirrhosis and even hepatocellular carcinoma [1]. Mutant viruses resistant against these drugs have emerged in vitro and in vivo, suggesting that several enzymatic activities or viral functions may have to be targeted in parallel in a combination approach, similar to the highly active antiretroviral therapy (HAART) against human immunodeficiency virus [3]. HCV is a small enveloped virus belonging to the Hepacivirus genus in the Flaviviridae family. It possesses a single positive-strand RNA genome encoding a long polyprotein which is processed by cellular and viral proteases into 10 different proteins, including structural proteins (core, E1, and E2) and non-structural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B). The essential role of NS2 in HCV lifecycle makes it an attractive target for antiviral therapies. The development of in vitro infectious HCV culture systems derived from genotype 2a (JFH1) and genotype 1a (H77S) has facilitated the study of HCV lifecycle and provides powerful tools for the discovery of novel antiviral drugs [9,10,11,12]
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