Abstract
Non‐structural protein 5A (NS5A) is a key regulator of the hepatitis C virus (HCV) life cycle including RNA replication, assembly and HCV internal ribosome entry site (IRES)‐mediated translation. We have previously identified an NS5A/heat shock protein 70 (HSP70) complex that is important for HCV IRES mediated translation. We have mapped the HSP70 interaction site on NS5A to a beta‐sheet hairpin in domain 1. Mutation of this site reduced NS5A‐augmented IRES‐mediated translation. We designed a cell permeable hairpin peptide derivative of this site which blocked NS5A/HSP70 complex formation in vitro compared to scrambled control. This peptide also inhibited IRES‐mediated translation, viral RNA replication and infectious virion production in a dose‐dependent manner. These results support the hypothesis that the NS5A/HSP70 complex is involved in IRES‐mediated translation and identify a sequence specific element in NS5A responsible for complex formation. Identification of this element will allow for further interrogation of NS5A‐mediated IRES activity, sequence specific HSP recognition and rational drug design.
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