Background:  Hepatitis C virus (HCV) entry is a multiple-step process involving a number of host factors and hence represents a promising target for new antiviral drug development.

Methods:  In search of novel inhibitors of HCV infection, we found that a human apolipoprotein E (apoE) peptide, hEP, containing both the receptor binding region, as well as the lipid binding region of apoE, specifically blocked the entry of cell culture grown HCV (HCVcc) at sub-micromolar concentrations.

Results:  hEP caused little cytotoxicity in vitro and remained active even if left 24 hours in cell culture. Interestingly, hEP did not inhibit HIV/HCV pseudotypes (HCVpp), nor did the peptide inhibit HIV or dengue virus infection. Further characterization mapped the anti-HCV activity to a 32-residue region that harbors the receptor binding domain of apoE. With the addition of a cysteine residue to the N-terminus to facilitate dimer formation, a peptide derived from this region effectively inhibited HCV infection. Finally, we demonstrated that hEP inhibited HCV entry by directly blocking the binding of virus to cell surface.

Conclusions:  ApoE peptides potently inhibit HCV infection and confirm a direct role of apoE in mediating HCV entry. Our findings also highlight the potential of developing novel entry inhibitors by targeting HCV–host interactions.