Iminosugars have therapeutic potential against a range of diseases, due to their efficacy as glycosidase inhibitors. A major challenge in the development of iminosugar drugs lies in making a compound that is selective for the glycosidase associated with a given disease. We report the synthesis of ToP-DNJ, an antiviral iminosugar-tocopherol conjugate. Tocopherol was incorporated into the design of the iminosugar in order to direct the drug to the liver and immune cells, specific tissues of interest for antiviral therapy. ToP-DNJ inhibits ER α-glucosidase II at low micromolar concentrations and selectively accumulates in the liver in vivo. In cellular assays, the drug showed efficacy exclusively in immune cells of the myeloid lineage. Taken together, these data demonstrate that inclusion of a native metabolite into an iminosugar provides selectivity with respect to target enzyme, target cell, and target tissue.

中文翻译：

---

ToP-DNJ，内质网α-葡萄糖苷酶II的选择性抑制剂，具有抗黄病毒活性。

氨基糖由于具有糖苷酶抑制剂的功效，因此具有治疗多种疾病的潜力。亚氨基糖药物开发中的主要挑战在于制备对与给定疾病相关的糖苷酶具有选择性的化合物。我们报告了ToP-DNJ的合成，一种抗病毒的亚氨基糖-生育酚偶联物。将生育酚掺入亚氨基糖的设计中，以便将药物导向肝脏和免疫细胞，这是抗病毒治疗的特定目标组织。ToP-DNJ在低微摩尔浓度下抑制ERα-葡萄糖苷酶II，并在体内选择性地积累在肝脏中。在细胞分析中，该药物仅在髓系谱系的免疫细胞中显示出功效。在一起