Abstract：
Hurler syndrome, a type of Mucopolysaccharidosis type I, is an inherited disorder caused by the accumulation of glycosaminoglycans (GAG) due to a deficiency in lysosomal α-L-iduronidase (IDUA), resulting in multiorgan dysfunction. In many patients with Hurler syndrome, IDUA proteins are not produced due to nonsense mutations in their genes; therefore, readthrough-inducing compounds, such as gentamycin, are expected to restore IDUA proteins by skipping the premature termination codon. In the present study, we synthesized a series of chromenopyridine derivatives to identify novel readthrough-inducing compounds. The readthrough-inducing activities of synthesized compounds were examined by measuring cellular IDUA activities and GAG concentrations in Hurler syndrome patient-derived cells. Compounds with a difluorophenyl group at the 2-position of chromenopyridine, a cyclobutyl group at the 3-position, and a basic side chain or basic fused ring exhibited excellent readthrough-inducing activities. KY-640, a chromenopyridine derivative with a tetrahydroisoquinoline sub-structure, increased the cellular IDUA activities of patient-derived cells by 3.2-fold at 0.3 µM and significantly reduced GAG concentrations, and also significantly increased enzyme activity in mouse models, suggesting its therapeutic potential in patients with Hurler syndrome.
摘要：
Hurler综合征,一种粘多糖贮积症I型,是由于溶酶体α-L-艾杜糖醛酸酶（IDUA）缺乏而导致的糖胺聚糖（GAG）积累引起的遗传性疾病，导致多器官功能障碍。在许多Hurler综合征患者中，IDUA蛋白不是由于其基因中的无义突变而产生的；因此，读取诱导化合物，比如庆大霉素，预期通过跳过提前终止密码子来恢复IDUA蛋白。在本研究中,我们合成了一系列的苯并吡啶甲酸衍生物，以鉴定新的可诱导连读的化合物。通过测量Hurler综合征患者来源细胞中的细胞IDUA活性和GAG浓度来检查合成化合物的通读诱导活性。在吡啶甲酸的2位具有二氟苯基的化合物，3位的环丁基，碱性侧链或碱性稠环表现出优异的读取诱导活性。KY-640，一种具有四氢异喹啉亚结构的吡啶甲酸衍生物，在0.3μM时，患者来源细胞的细胞IDUA活性增加3.2倍，GAG浓度显着降低，并且在小鼠模型中也显著增加了酶活性，提示其在Hurler综合征患者中的治疗潜力。
