“DAA, direct-acting antiviral agents; HCV, hepatitis C vir


“DAA, direct-acting antiviral agents; HCV, hepatitis C virus; ISDR, interferon-alpha sensitivity determining region. Hepatitis C virus (HCV) is a major cause of liver disease and mortality affecting 170 million people worldwide.1 check details Chronic infection with HCV can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma2 and is the most common reason for liver transplantation in the United States.3 HCV is an enveloped single-strand RNA virus that belongs to the flaviviridae family. It has a 9.6-kb RNA genome encoding a single polyprotein of 3,010 amino acids. This polyprotein is composed of structural

and nonstructural proteins. HCV entry into hepatocytes is mediated by the structural proteins, including glycoproteins E1 and E2, which interact with cellular receptors. Once HCV enters the host Gefitinib cell, replication of its genome is orchestrated by the nonstructural proteins, including proteases (NS2-3, NS3-4A), helicases (NS3), polymerases (NS5B), and NS5A,

a protein with no known enzymatic activity.4-6 NS5A is essential to the replication machinery of the virus and critical in the assembly of infectious viral particles. However, its specific role remains unclear.6 A number of properties of this viral protein have been described. NS5A interacts with a variety of host proteins, including some which modulate host cellular Protein tyrosine phosphatase signaling pathways.7, 8 Studies have demonstrated that NS5A interacts with p53 and p21, affecting

cell cycle control.7 More recently, NS5A was found to interact with proteins related to focal adhesions, gap-junction, and host signaling pathways.7, 8 NS5A also interacts with other nonstructural viral proteins. During HCV viral replication, NS5A interacts with the RNA- dependent RNA-polymerase NS5B, which is essential to maintain HCV replication in cell culture. Through its domain 1 NS5A has RNA-binding capacity, a property that can be critical for RNA replication.9 In addition to being involved in HCV replication, NS5A is involved in the assembly of the virus by forming stable complexes with NS2, the main protein involved in HCV assembly.10 NS5A attracted attention due to its interferon-alpha sensitivity determining region (ISDR), which can confer resistance to interferon treatment. Moreover, NS5A has an effect on interferon activity by up-regulating interleukin (IL)-8, which has been reported to attenuate the antiviral properties of interferon.11 These observations suggest that NS5A plays a critical role in many aspects of the life cycle of HCV and is therefore an attractive target for antiviral therapy (Fig. 1). Until recently, the standard treatment for HCV infection has been pegylated interferon-alpha and ribavirin. These drugs have significant and often serious side effects.

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