Wang Leah Liu, Estrada Leslie, Wiggins Joshua, Anantpadma Manu, Patten J J, Davey Robert A, Xiang Shi-Hua
School of Veterinary Medicine and Biomedical Sciences, USA; Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE, 68583, USA.
Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE, 68583, USA; School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, NE, 68583, USA.
Antiviral Res. 2022 Oct;206:105399. doi: 10.1016/j.antiviral.2022.105399. Epub 2022 Aug 22.
Filoviruses enter cells through macropinocytosis and trafficking into the endosomes in which they bind to the receptor Niemann-Pick C1 protein (NPC1) for membrane fusion and entry into the cytoplasm. The endosomal receptor-binding is critical step for filovirus entry. Designing inhibitors to block receptor binding will prevent viral entry. Using available binding structural information from the co-crystal structures of the viral GP with the receptor NPC1 or with monoclonal antibodies, we have conducted structure-based design of peptide inhibitors to target the receptor binding site (RBS). The designed peptides were tested for their inhibition activity against pseudo-typed or replication-competent viruses in a cell-based assay. The results indicate that these peptides exhibited strong activities against both Ebola and Marburg virus infection. It is expected that these peptides can be further developed for therapeutic use to treat filovirus infection and combat the outbreaks.
丝状病毒通过巨胞饮作用进入细胞，并转运至内体，在那里它们与受体尼曼-皮克C1蛋白（NPC1）结合，进行膜融合并进入细胞质。内体受体结合是丝状病毒进入的关键步骤。设计抑制剂阻断受体结合将阻止病毒进入。利用病毒糖蛋白（GP）与受体NPC1或单克隆抗体的共晶体结构中可用的结合结构信息，我们进行了基于结构的肽抑制剂设计，以靶向受体结合位点（RBS）。在基于细胞的试验中测试了设计的肽对假型或具有复制能力的病毒的抑制活性。结果表明，这些肽对埃博拉病毒和马尔堡病毒感染均表现出强大的活性。预计这些肽可进一步开发用于治疗丝状病毒感染和应对疫情爆发的治疗用途。
