Many viruses use endosomal pathways to gain entry into cells and propagate infection. Sensing of endosomal acidification is a trigger for the release of many virus cores into the cell cytosol. Previous efforts with inhibitors of vacuolar ATPase have been shown to block endosomal acidification and affect viral entry, albeit with limited potential for therapeutic selectivity. In this study, four novel series of derivatives of the vacuolar ATPase inhibitor diphyllin were synthesized to assess their potential for enhancing potency and anti-filoviral activity over cytotoxicity. Derivatives that suitably blocked cellular entry of Ebola pseudotyped virus were further evaluated as inhibitors of endosomal acidification and isolated human vacuolar ATPase activity. Several compounds with significant increases in potency over diphyllin in these assays also separated from cytotoxic doses in human cell models by >100-fold. Finally, three derivatives were shown to be inhibitors of replication-competent Ebola viral entry into primary macrophages with similar potencies and enhanced selectivity toward antiviral activity.

中文翻译：

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通过液泡 (H+)-ATPase 抑制作用阻断丝状病毒细胞进入的 Diphyllin 衍生物的表型优先级。

许多病毒使用内体途径进入细胞并传播感染。内体酸化的感觉是许多病毒核心释放到细胞溶质中的触发因素。先前使用液泡 ATP 酶抑制剂的努力已被证明可以阻断内体酸化并影响病毒进入，尽管治疗选择性的潜力有限。在这项研究中，合成了液泡 ATP 酶抑制剂 diphyllin 的四个新系列衍生物，以评估它们在增强效力和抗丝病毒活性超过细胞毒性方面的潜力。适当地阻止埃博拉假型病毒进入细胞的衍生物被进一步评估为内体酸化和分离的人类液泡 ATP 酶活性的抑制剂。在这些测定中，与敌草素相比，效力显着增加的几种化合物也与人类细胞模型中的细胞毒性剂量分开 > 100 倍。最后，三种衍生物被证明是具有复制能力的埃博拉病毒进入初级巨噬细胞的抑制剂，具有相似的效力和增强的抗病毒活性选择性。