Human apolipoprotein E peptides inhibit hepatitis C virus entry by blocking virus binding.
Human apolipoprotein E peptides inhibit hepatitis C virus entry by blocking virus binding.
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DOI：
10.1002/hep.25665
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发表时间：
2012-08
期刊：
影响因子：
13.5
通讯作者：
Wang, Tianyi
中科院分区：
文献类型：
--
作者：
Liu, Shufeng;McCormick, Kevin D.;Zhao, Wentao;Zhao, Ting;Fan, Daping;Wang, Tianyi
丙型肝炎病毒（HCV）进入是一个多步骤的过程，涉及许多宿主因素，因此代表了一个有前途的新的抗病毒药物开发的目标。在寻找新的HCV感染抑制剂的过程中，我们发现人载脂蛋白E（apoE）肽，hEP，含有apoE的受体结合片段和脂质结合片段，在亚微摩尔浓度下特异性地阻断细胞培养生长的HCV（HCVRNA）的进入。hEP在体外引起的细胞毒性很小，即使在细胞培养物中放置24小时也保持活性。有趣的是，hEP既不抑制HIV-HCV假型（HCVpp），也不抑制HIV和登革病毒（DENV）感染。进一步的表征映射的抗HCV活性的32个残基的区域，窝藏apoE的受体结合结构域，但该片段必须包含一个半胱氨酸残基在N-末端介导二聚体的形成。该肽的抗HCV活性似乎取决于其长度和序列，并与其结合脂质的能力相关。最后，我们证明了apoE衍生的肽直接阻断HCV 4和患者血清衍生的病毒与肝癌细胞以及原代人肝细胞的结合。apoE肽有效地抑制HCV感染，并提示apoE在介导HCV进入中的直接作用。我们的研究结果还强调了通过靶向HCV-宿主相互作用开发apoE模拟肽作为新型HCV进入抑制剂的潜力。
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. In search of novel inhibitors of HCV infection, we found that a human apolipoprotein E (apoE) peptide, hEP, containing both a receptor binding fragment and a lipid binding fragment of apoE, specifically blocked the entry of cell culture grown HCV (HCVcc) at sub-micromolar concentrations. hEP caused little cytotoxicity in vitro and remained active even if left 24 hours in cell culture. Interestingly, hEP inhibited neither HIV-HCV pseudotypes (HCVpp) nor HIV and Dengue virus (DENV) infection. Further characterization mapped the anti-HCV activity to a 32-residue region that harbors the receptor binding domain of apoE, but this fragment must contain a cysteine residue at the N-terminus to mediate dimer formation. The anti-HCV activity of the peptide appears to be dependent on both its length and sequence and correlates with its ability to bind lipids. Finally, we demonstrated that the apoE-derived peptides directly blocked the binding of both HCVcc and patient serum-derived virus to hepatoma cells as well as primary human hepatocytes. apoE peptides potently inhibit HCV infection and suggest a direct role of apoE in mediating HCV entry. Our findings also highlight the potential of developing apoE mimetic peptides as novel HCV entry inhibitors by targeting HCV-host interactions.
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