Structure-Based Design of Peptide Entry Inhibitors against Ebola Virus Infection

摘要 埃博拉病毒（EBOV）与马尔堡病毒（MARV）一起沿着属于丝状病毒科， 感染人类和非人灵长类动物，并引起爆发，死亡率高达90%。 我们没有批准的药物来治疗这种致命的病毒性疾病，因此迫切需要 开发治疗方法来应对危险的疾病爆发。在这个项目中，我们建议开发 靶向受体结合位点（RBS）的肽基抑制剂，以阻断病毒感染。我们将 使用NPC 1受体的可用共晶结构进行基于结构的设计，或 与病毒糖蛋白结合的单克隆抗体。初始评估将使用伪 分型病毒以在基于细胞的测定中测试病毒进入。这些肽中最好的候选肽 随后将在BSL-4防护设施中使用可复制的 病毒进入抑制试验。合格候选物的体内评价将在 病毒攻击小鼠模型以测量保护效力。在所有这些评估之后， 有希望的候选人可以推进到非人类灵长类动物或人类临床试验。

Abstract Ebola viruses (EBOV) along with Marburg viruses (MARV) belong to the Filoviridae family which infects humans and nonhuman primates and causes outbreaks with a high mortality up to 90%. We do not have approved drugs for treating this deadly viral disease and therefore it is urgent to develop therapeutics to cope with the dangerous outbreaks. In this project, we propose to develop peptide based inhibitors targeting the receptor binding site (RBS) to block viral infection. We will conduct structure based design using the available co-crystal structures of the NPC1 receptor or monoclonal antibodies bound to the viral glycoprotein. The initial evaluation will utilize pseudo- typed viruses to test viral entry in a cell based assay. The best peptide candidates from these assays will subsequently be tested in a BSL-4 containment facility using replication competent viruses for entry inhibition tests. In vivo evaluations of qualified candidates will be conducted in a virus challenge mouse model to measure protection efficacy. After all these evaluations, promising candidates could be advanced to nonhuman primates or human clinical trials.