Marugan Juan J., Zheng Wei, Ferrer Marc, Motabar Omid, Southall Noel, Goldin Ehud, Westbroek Wendy, Sidransky Ellen
NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, United States.
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Building 35 Rm1A213, 35 Convent Drive, Bethesda, Maryland 20892, United States.
Glycogen storage disease II, or Pompe disease, is a rare and often fatal autosomal recessive lysosomal storage disorder (LSD) caused by the dysfunction of the lysosomal enzyme acid alpha-glucosidase (GAA). Accumulation of GAA’s substrate, glycogen, causes enlargement of cellular lysosomes, adversely affecting many cells, especially heart and skeletal muscle tissues. The only FDA approved treatment for Pompe disease is enzyme replacement therapy, called Myozyme, which has significant limitations. Importantly, of the over 100 different mutations known to cause Pompe disease, many retain enzymatic activity , although the structural changes induced by mutants affect trafficking of the enzyme to the lysosome. Small molecule chaperones can be used to correct this trafficking defect. These compounds bind to the protein in the endoplasmic reticulum, accelerating the folding process and increasing their translocation to the lysosome, thereby reducing substrate accumulation. Several iminosugar inhibitors of GAA, such duvoglustat, are known to chaperone the translocation of mutant GAA proteins. However, their impact on substrate reduction may be limited by their continued inhibition of the target enzyme, as well as limited selectivity towards GAA. We have previously reported an inhibitor (ML201) and through further work, we have now also identified the first non-inhibitory small molecule chaperone of acid alpha glucosidase, ML247. Here, we demonstrate that ML247 enhances mutant enzyme translocation using Pompe patient-derived fibroblasts. ML247 displays reasonable pharmacokinetics and might serve as a pivotal first step in efforts to develop a non-inhibitory molecular chaperone for the treatment of Pompe disease.
糖原贮积病II型，即庞贝病，是一种罕见且常致命的常染色体隐性溶酶体贮积症（LSD），由溶酶体酶酸性α-葡萄糖苷酶（GAA）功能障碍引起。GAA底物糖原的积累导致细胞溶酶体增大，对许多细胞产生不利影响，尤其是心脏和骨骼肌组织。美国食品药品监督管理局（FDA）批准的唯一用于治疗庞贝病的方法是酶替代疗法，即美而赞（Myozyme），但该疗法有显著局限性。重要的是，在已知导致庞贝病的100多种不同突变中，许多突变仍保留酶活性，尽管突变体诱导的结构变化会影响酶向溶酶体的转运。小分子伴侣可用于纠正这种转运缺陷。这些化合物在内质网中与蛋白质结合，加速折叠过程并增加其向溶酶体的转运，从而减少底物积累。已知几种GAA的亚氨基糖抑制剂，如度伐鲁司他，可辅助突变GAA蛋白的转运。然而，它们对底物减少的影响可能受到其对靶酶的持续抑制以及对GAA的有限选择性的限制。我们之前报道过一种抑制剂（ML201），通过进一步研究，我们现在还鉴定出了酸性α-葡萄糖苷酶的首个非抑制性小分子伴侣ML247。在此，我们利用庞贝病患者来源的成纤维细胞证明ML247可增强突变酶的转运。ML247具有合理的药代动力学性质，可能是开发用于治疗庞贝病的非抑制性分子伴侣的关键第一步。
