MOH Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Hepatology. 2012 Aug;56(2):507-15. doi: 10.1002/hep.25685. Epub 2012 Jun 11.
Hepatitis C virus (HCV) entry is a complicated process that requires multiple host factors, such as CD81, scavenger receptor BI, claudin-1 (CLDN1), and occludin. The interaction of virus and cellular entry factors represents a promising target for novel anti-HCV drug development. In this study, we sought to identify peptide inhibitors for HCV entry by screening a library of overlapping peptides covering the four above-mentioned entry factors. An 18-amino acid peptide (designated as CL58) that was derived from the CLDN1 intracellular and first transmembrane region inhibited both de novo and established HCV infection in vitro. Unlike previously reported peptides corresponding to CLDN1 extracellular loops, CL58 did not alter the normal distribution of CLDN1 and was not cytotoxic in vitro at concentrations nearly 100-fold higher than the effective antiviral dose. The inhibitory effect of CL58 appeared to occur at a late step during viral entry, presumably after initial binding. Finally, overexpressed CL58 was able to interact with HCV envelope proteins.
We identified a novel CLDN1-derived peptide that inhibits HCV entry at a postbinding step. The findings expand our knowledge of the roles that CLDN1 play in HCV entry and highlight the potential for developing a new class of inhibitors targeting the viral entry process.
丙型肝炎病毒 (HCV) 进入是一个复杂的过程，需要多个宿主因素，如 CD81、清道夫受体 BI、 Claudin-1 (CLDN1) 和 Occludin。病毒与细胞进入因子的相互作用代表了开发新型抗 HCV 药物的有前途的目标。在这项研究中，我们通过筛选涵盖上述四个进入因子的重叠肽文库，旨在寻找 HCV 进入的肽抑制剂。一种源自 CLDN1 细胞内和第一跨膜区的 18 个氨基酸肽（命名为 CL58），在体外抑制新形成和已建立的 HCV 感染。与以前报道的对应于 CLDN1 细胞外环的肽不同，CL58 不会改变 CLDN1 的正常分布，并且在体外的细胞毒性浓度比有效抗病毒剂量高近 100 倍。CL58 的抑制作用似乎发生在病毒进入的后期步骤，大概在初始结合之后。最后，过表达的 CL58 能够与 HCV 包膜蛋白相互作用。
我们鉴定了一种新型的 CLDN1 衍生肽，它在结合后抑制 HCV 进入。这些发现扩展了我们对 CLDN1 在 HCV 进入中的作用的认识，并强调了开发针对病毒进入过程的新型抑制剂的潜力。
