ToP-DNJ, a Selective Inhibitor of Endoplasmic Reticulum α-Glucosidase II Exhibiting Antiflaviviral Activity.,ACS Chemical Biology

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ToP-DNJ, a Selective Inhibitor of Endoplasmic Reticulum α-Glucosidase II Exhibiting Antiflaviviral Activity.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2017-12-05 , DOI: 10.1021/acschembio.7b00870
J L Kiappes ₁ , Michelle L Hill ₁ , Dominic S Alonzi ₁ , Joanna L Miller ₁ , Ren Iwaki ₂ , Andrew C Sayce ₁ , Alessandro T Caputo ₁ , Atsushi Kato ₂ , Nicole Zitzmann ₁

Affiliation

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，一种内质网 α-葡萄糖苷酶 II 的选择性抑制剂，具有抗黄病毒活性。

由于亚氨基糖作为糖苷酶抑制剂的功效，因此具有治疗多种疾病的潜力。亚氨基糖药物开发的一个主要挑战在于制造一种对与特定疾病相关的糖苷酶具有选择性的化合物。我们报道了 ToP-DNJ 的合成，这是一种抗病毒亚氨基糖-生育酚缀合物。生育酚被纳入亚氨基糖的设计中，以便将药物引导至肝脏和免疫细胞，以及抗病毒治疗感兴趣的特定组织。 ToP-DNJ 在低微摩尔浓度下抑制 ER α-葡萄糖苷酶 II，并选择性地在体内积累在肝脏中。在细胞测定中，该药物仅对骨髓谱系的免疫细胞显示出功效。总而言之，这些数据表明，将天然代谢物纳入亚氨基糖中提供了针对靶酶、靶细胞和靶组织的选择性。

更新日期：2017-12-05

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