Developments in Cell-Penetrating Peptides as Antiviral Agents and as Vehicles for Delivery of Peptide Nucleic Acid Targeting Hepadnaviral Replication Pathway.

Bénédicte Ndeboko,Olivier Hantz,Lucyna Cova,Guy Lemamy

doi:10.3390/biom8030055

Bénédicte Ndeboko, Olivier Hantz + Show 2 more

Open Access

https://doi.org/10.3390/biom8030055

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Abstract

Alternative therapeutic approaches against chronic hepatitis B virus (HBV) infection need to be urgently developed because current therapies are only virostatic. In this context, cell penetration peptides (CPPs) and their Peptide Nucleic Acids (PNAs) cargoes appear as a promising novel class of biologically active compounds. In this review we summarize different in vitro and in vivo studies, exploring the potential of CPPs as vehicles for intracellular delivery of PNAs targeting hepadnaviral replication. Thus, studies conducted in the duck HBV (DHBV) infection model showed that conjugation of (D-Arg)8 CPP to PNA targeting viral epsilon (ε) were able to efficiently inhibit viral replication in vivo following intravenous administration to ducklings. Unexpectedly, some CPPs, (D-Arg)8 and Decanoyl-(D-Arg)8, alone displayed potent antiviral effect, altering late stages of DHBV and HBV morphogenesis. Such antiviral effects of CPPs may affect the sequence-specificity of CPP-PNA conjugates. By contrast, PNA conjugated to (D-Lys)4 inhibited hepadnaviral replication without compromising sequence specificity. Interestingly, Lactose-modified CPP mediated the delivery of anti-HBV PNA to human hepatoma cells HepaRG, thus improving its antiviral activity. In light of these promising data, we believe that future studies will open new perspectives for translation of CPPs and CPP-PNA based technology to therapy of chronic hepatitis B.

Highlights

Hepatitis B virus (HBV) infection is still a major public health issue, with over 240 million virus carriers worldwide
Our preliminary findings demonstrated that treatment of hepatitis B virus (HBV)-infected HepaRG cells by cell penetration peptides (CPPs)-Peptide Nucleic Acids (PNAs) conjugate coupled to Lactose inhibited HBV surface antigen (HBsAg) release
Different studies demonstrated an important role of CPPs or modified-CPPs in the intracellular delivery of PNAs that target the hepadnaviral replication pathway

Summary

Introduction

Hepatitis B virus (HBV) infection is still a major public health issue, with over 240 million virus carriers worldwide. During investigation of CPP-PNAs conjugates as novel anti-HBV agents, we surprisingly discovered that (D-Arg) peptide alone was able to inhibit hepadnaviral replication [10,23] This finding prompted us to initiate in vitro and in vivo studies in a DHBV infection model to better understand the antiviral action of such CPPs [10,23]. The i.v administration of (DArg) alone to DHBV-infected ducklings resulted in a decrease in viremia, confirming the ability of this CPP to inhibit hepadnaviral replication (as detailed above) These findings indicate that anti-DHBV activity exhibited by (DArg) CPP alone may explain the limited sequence specificity of this CPP-PNA conjugate. The single-chain antibody targeting the hepatitis B core protein and coupled to the CPP was internalized into HepG2.2.15 cells and inhibited HBV replication in vitro [25]

Sugar Modified CPP-PNA Uptake and Their Anti-HBV Activity in HepaRG Cells

Uptake of FITC-Lac-PNAin in HepaRG

Antiviral Activity of CPP-Based Approaches against Other Viruses

Findings

Conclusions