ASGP-Receptors in the Delivery of PNA Targeting Replication Pathaway of Hepadnaviruses in HepaRG Cell Line

Peptide nucleic acids (PNAs) are a new class of acid nucleic mimics which represent an extremely powerful tool against hepatitis B virus (HBV). Because the major problem of PNA application as antiviral drugs is their poor intracellular uptake, we chose the sugars for their coupling. Thus, we investigated, the ability of PNA targeting Hepatitis B surface protein and DR1 region, coupled to sugars to inhibit HBV replication in HepaRG cells line. The results obtained show that anti-S PNA coupled to lactose specifically inhibit viral replication. By contrast the same PNA coupled to Mannose inhibited viral replication in a not sequence-specific manner, since its corresponding mismatch coupled to the same sugar (Mannose) exhibited an anti-HBV activity. Surprisingly, an another PNA targeting DR1 HBV region and coupled to the same Mannose, led to a specific inhibition of viral replication. This result demonstrated that if the choice of sugar used as vehicle for PNA uptake may play an important role, the nature of PNA can influence or minimize the effect of coupling on the specificity of their antiviral activity. Taken together, we provide here the first evidence that sugar-PNA conjugates can enter into HepaRG cells line and inhibit hepadnaviral replication, without inducing toxicity.