Kiappes J L, Hill Michelle L, Alonzi Dominic S, Miller Joanna L, Iwaki Ren, Sayce Andrew C, Caputo Alessandro T, Kato Atsushi, Zitzmann Nicole
Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, U.K.
Department of Hospital Pharmacy, University of Toyama , 2630 Sugitani, Toyama 930-0194, Japan.
ACS Chem Biol. 2018 Jan 19;13(1):60-65. doi: 10.1021/acschembio.7b00870. Epub 2017 Dec 5.
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.
由于其作为糖苷酶抑制剂的功效，亚氨基糖对一系列疾病具有治疗潜力。亚氨基糖药物开发中的一个主要挑战在于制备一种对与特定疾病相关的糖苷酶具有选择性的化合物。我们报道了抗病毒亚氨基糖-生育酚缀合物ToP-DNJ的合成。将生育酚纳入亚氨基糖的设计中，以便将药物导向肝脏和免疫细胞，这是抗病毒治疗中感兴趣的特定组织。ToP-DNJ在低微摩尔浓度下抑制内质网α-葡萄糖苷酶II，并在体内选择性地在肝脏中积累。在细胞试验中，该药物仅在髓系谱系的免疫细胞中显示出疗效。综上所述，这些数据表明将天然代谢物纳入亚氨基糖可在靶酶、靶细胞和靶组织方面提供选择性。
