α-Glucosidase inhibitors are potential therapeutics for the treatment of diabetes, viral infections, and Pompe disease. Herein, we report a 1,6-epi-cyclophellitol cyclosulfamidate as a new class of reversible α-glucosidase inhibitors that displays enzyme inhibitory activity by virtue of its conformational mimicry of the substrate when bound in the Michaelis complex. The α-d-glc-configured cyclophellitol cyclosulfamidate 4 binds in a competitive manner the human lysosomal acid α-glucosidase (GAA), ER α-glucosidases, and, at higher concentrations, intestinal α-glucosidases, displaying an excellent selectivity over the human β-glucosidases GBA and GBA2 and glucosylceramide synthase (GCS). Cyclosulfamidate 4 stabilizes recombinant human GAA (rhGAA, alglucosidase alfa, Myozyme) in cell medium and plasma and facilitates enzyme trafficking to lysosomes. It stabilizes rhGAA more effectively than existing small-molecule chaperones and does so in vitro, in cellulo, and in vivo in zebrafish, thus representing a promising therapeutic alternative to Miglustat for Pompe disease.

中文翻译：

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1,6-epi-Cyclophellitol Cyclosulfamidate 是一种真正的溶酶体 α-葡萄糖苷酶稳定剂，用于治疗庞贝病

α-葡萄糖苷酶抑制剂是治疗糖尿病、病毒感染和庞贝病的潜在疗法。在此，我们报道了一种 1,6-表- 环酚醇环磺酰胺酯作为一类新的可逆 α-葡糖苷酶抑制剂，其在与 Michaelis 复合物结合时具有与底物的构象模拟，从而显示出酶抑制活性。α - d - glc-构型的环芳醇环磺酰胺4以竞争性方式结合人溶酶体酸α-葡糖苷酶(GAA)、ERα-葡糖苷酶，并且在较高浓度下，与肠道α-葡糖苷酶结合，显示出优于人的选择性β-葡萄糖苷酶 GBA 和 GBA2 以及葡萄糖神经酰胺合酶 (GCS)。环磺胺4稳定细胞培养基和血浆中的重组人 GAA（rhGAA、阿糖苷酶 alfa、Myozyme）并促进酶转运至溶酶体。它比现有的小分子伴侣更有效地稳定 rhGAA ，并且在斑马鱼的体外、纤维素和体内都可以做到这一点，因此代表了 Miglustat 治疗庞贝病的有希望的治疗替代品。