title: Screening and rational design of hepatitis C virus entry inhibitory peptides derived from GB virus A NS5A.
abstract: Chronic infection by hepatitis C virus (HCV) is a cause of the global burden of liver diseases. HCV entry into hepatocytes is a complicated and multistep process that represents a promising target for antiviral intervention. The recently reported amphipathic α-helical virucidal peptide (C5A) from the HCV NS5A protein suggests a new category of antiviral drug candidates. In this study, to identify C5A-like HCV inhibitors, synthetic peptides derived from the C5A-corresponding NS5 protein region of selected Flaviviridae viruses were evaluated for their anti-HCV activities. A peptide from GB virus A (GBV-A), but not other flaviviruses, demonstrated an inhibitory effect on HCV infection. Through a series of sequence optimizations and modifications of the peptide helicity and hydrophobicity, we obtained a peptide designated GBVA10-9 with highly potent anti-HCV activity. GBVA10-9 suppressed infection with both cell culture-derived and pseudotyped HCV in vitro, and the 50% cell culture inhibitory concentration ranged from 20 nM to 160 nM, depending on the genotypic origin of the envelope proteins. GBVA10-9 had no detectable effects on either HCV attachment to Huh7.5.1 cells or viral RNA replication. No virucidal activity was found with GBVA10-9, suggesting an action mechanism distinct from that of C5A. The inhibitory effect of GBVA10-9 appeared to occur at the postbinding step during viral entry. Taken together, the results with GBVA10-9 demonstrated a potent activity for blocking HCV entry that might be used in combination with other antivirals directly targeting virus-encoded enzymes. Furthermore, GBVA10-9 also provides a novel tool to dissect the detailed mechanisms of HCV entry.
authors.affiliation: MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Liu
authors.forename: Yibing
authors.initials: Y
authors.lastname: Huang
authors.forename: Min
authors.initials: M
authors.lastname: Cheng
authors.forename: Ling
authors.initials: L
authors.lastname: Pan
authors.forename: Youhui
authors.initials: Y
authors.lastname: Si
authors.forename: Guirong
authors.initials: G
authors.lastname: Li
authors.forename: Yuqiang
authors.initials: Y
authors.lastname: Niu
authors.forename: Lianjing
authors.initials: L
authors.lastname: Zhao
authors.forename: Jin
authors.initials: J
authors.lastname: Zhao
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
mesh_terms: D000998:Antiviral Agents / Q000302:isolation & purification* / Q000494:pharmacology; D001688:Biological Products / Q000302:isolation & purification* / Q000494:pharmacology; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D029405:GB virus A / Q000235:genetics*; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000235:genetics / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000494:pharmacology*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D001688:Biological Products; D010455:Peptides; D017361:Viral Nonstructural Proteins