Therapeutic Potential of Cell Penetrating Peptides (CPPs) and Cationic Polymers for Chronic Hepatitis B.

Peter Nielsen,Bénédicte Ndeboko,Guy Lemamy,Lucyna Cova

doi:10.3390/ijms161226094

Abstract

Chronic hepatitis B virus (HBV) infection remains a major health problem worldwide. Because current anti-HBV treatments are only virostatic, there is an urgent need for development of alternative antiviral approaches. In this context, cell-penetrating peptides (CPPs) and cationic polymers, such as chitosan (CS), appear of particular interest as nonviral vectors due to their capacity to facilitate cellular delivery of bioactive cargoes including peptide nucleic acids (PNAs) or DNA vaccines. We have investigated the ability of a PNA conjugated to different CPPs to inhibit the replication of duck hepatitis B virus (DHBV), a reference model for human HBV infection. The in vivo administration of PNA-CPP conjugates to neonatal ducklings showed that they reached the liver and inhibited DHBV replication. Interestingly, our results indicated also that a modified CPP (CatLip) alone, in the absence of its PNA cargo, was able to drastically inhibit late stages of DHBV replication. In the mouse model, conjugation of HBV DNA vaccine to modified CS (Man-CS-Phe) improved cellular and humoral responses to plasmid-encoded antigen. Moreover, other systems for gene delivery were investigated including CPP-modified CS and cationic nanoparticles. The results showed that these nonviral vectors considerably increased plasmid DNA uptake and expression. Collectively promising results obtained in preclinical studies suggest the usefulness of these safe delivery systems for the development of novel therapeutics against chronic hepatitis B.

Highlights

Chronic hepatitis B virus (HBV) infection remains one of the most serious health problems worldwide, despite the availability of a prophylactic vaccine
Current therapeutic strategies approved for chronic hepatitis B treatment can be divided into two groups according to their mechanism of action; immunomodulation agents such as standard and pegylated interferon-α (IFN-α) and oral nucleoside analogues (NUCs) including lamivudine (LAM), telbivudine (LdT), entecavir (ETV), adefovir dipivoxil (ADV) and tenofovir dipivoxil fumarate (TDF) [3]
Because the encapsidation signal ε plays a key role in the initiation of HBV reverse transcription [36,38], we have investigated the ability of an antisense peptide nucleic acids (PNAs) targeting this ε to inhibit viral replication in the duck hepatitis B virus (DHBV) infection model

Summary

Introduction

Chronic hepatitis B virus (HBV) infection remains one of the most serious health problems worldwide, despite the availability of a prophylactic vaccine. Development of alternative therapeutic approaches for chronic HBV infection is urgently needed [4] In this regard, cell-penetrating peptides (CPPs), known as protein transduction domains (PTDs) or membrane translocation sequences (MTSs) represent one of the most promising molecular mechanisms for passive delivery of biologically active molecules into the cells [5]. Because current NUCs-based antiviral treatments cannot eliminate viral cccDNA from infected hepatocytes and lead to the selection of resistant mutants, alternative approaches such as antisense PNAs or DNA vaccines, targeting different steps of HBV replication cycle, appear of particular value for chronic hepatitis B therapy

Effect of CPP-PNA Conjugates on DHBV Replication

Benefit of Chitosan-Mediated Gene Uptake

Findings

Conclusions