Targeting the Hepatitis C Virus with PNAs

Abstract

The liver specific microRNA-122 (miR-122) has been shown to facilitate the replication and/or translation of the Hepatitis C virus (HCV). Although the exact role played by miR-122 in this process is not fully understood, it has been shown that one of the functions of miR-122 is to stabilize the HCV RNA genome. It has also been shown that miR-122 is a valid antiviral target, as locked nucleic acids (LNAs) developed against miR-122 abolished HCV replication. However, miR-122 has numerous other functions in the hepatic cell, which will also be affected by LNAs. In this study, we adopted a different approach by designing peptide nucleic acids (PNAs) against the highly conserved miR-122 binding sites within the HCV genome, and tested their antiviral properties. We demonstrated the ability of the PNA to bind specifically the 5' UTR of the HCV genome, with a low nanomolar dissociation constant. Moreover, we showed that the PNA is able to invade the HCV 5'-UTR - miR-122 complex displacing miR-122, and thus preventing it from exerting its beneficial function upon HCV replication and/or translation.