Abstract
Viral infection is an early stage of its life cycle and represents a promising target for antiviral drug development. Here we designed and characterized three peptide inhibitors of hepatitis C virus (HCV) infection based on the structural features of the membrane-associated p7 polypeptide of HCV. The three peptides exhibited low toxicity and high stability while potently inhibiting initial HCV infection and suppressed established HCV infection at non-cytotoxic concentrations in vitro. The most efficient peptide (designated H2-3), which is derived from the H2 helical region of HCV p7 ion channel, inhibited HCV infection by inactivating both intracellular and extracellular viral particles. The H2-3 peptide inactivated free HCV with an EC50 (50% effective concentration) of 82.11 nm, which is >1000-fold lower than the CC50 (50% cytotoxic concentration) of Huh7.5.1 cells. H2-3 peptide also bound to cell membrane and protected host cells from viral infection. The peptide H2-3 did not alter the normal electrophysiological profile of the p7 ion channel or block viral release from Huh7.5.1 cells. Our work highlights a new anti-viral peptide design strategy based on ion channel, giving the possibility that ion channels are potential resources to generate antiviral peptides.
Highlights
Membrane-associated viral proteins are potential resources to generate antiviral peptides
These results suggest that H2-3 peptide most likely interacts with both virus and host cells, thereby blocking the viral entry step, which generates a comprehensive inhibitory effect on an established viral infection
H2-3 peptide efficiently adsorbed to Huh7.5.1 cells after 4 h of incubation and the initially internalized virus was reduced by 74% (Fig. 6B), whereas after 24 h of incubation, H2-3 peptide entered Huh7.5.1 cells and located in the cytoplasm. At this time of pretreatment, initially internalized virus was still reduced by 56% (Fig. 6B). These results suggest that H2-3 peptide potently inhibits initial hepatitis C virus (HCV) infection by binding to cell surface, and the inhibitory effect slightly decreased when the cell-bound peptide was gradually internalized
Summary
Membrane-associated viral proteins are potential resources to generate antiviral peptides. A peptide mimetic of an essential region of gp, which is involved in fusion, has been successfully developed as an antiviral agent against HIV infection [12] Another peptide containing a portion of the HCV E2 transmembrane domain inhibits HCV pseudoparticle infection [10]. The amphipathic ␣-helical peptide C5A, which was derived from the membrane anchor domain of the HCV NS5A protein, showed significant inhibitory effects against HCV, HIV, and HSV infection in vitro [13,14,15] Some of these peptides selectively and reversibly blocked viral infection without inactivating virions, whereas the effects of other peptides were not readily distinguishable from virus inactivation. Our work opens a new avenue for screening anti-HCV peptides and uncovers potential anti-HCV agents
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