A Bicyclic 1-Deoxygalactonojirimycin Derivative as a Novel Pharmacological Chaperone for GM(1) Gangliosidosis

作者：Takai Tomoko; Higaki Katsumi^*; Aguilar Moncayo Matilde; Mena Barragan Teresa; Hirano Yuki; Yura Kei; Yu Liang; Ninomiya Haruaki; Isabel Garcia Moreno M; Sakakibara Yasubumi; Ohno Kousaku; Nanba Eiji; Ortiz Mellet Carmen; Garcia Fernandez Jose M; Suzuki Yoshiyuki

来源：Molecular Therapy, 2013, 21(3): 526-532.

DOI：10.1038/mt.2012.263

Lysosonnal beta-galactosidase (beta-Gal) deficiency causes a group of disorders that include neuronopathic GM(1) gangliosidosis and non-neuronopathic Morquio B disease. We have previously proposed the use of small molecule ligands of beta-Gal as pharmacological chaperones (PCs) for the treatment of GM(1) gangliosidosis brain pathology. Although it is still under development, PC therapy has yielded promising preclinical results in several lysosomal diseases. In this study, we evaluated the effect of bicyclic 1-deoxygalactonojirimycin (DGJ) derivative of the sp(2)-iminosugar type, namely 5N,6S-(N%26apos;-butyliminomethylidene)-6-thio-1-deoxygalactonojirimycin (6S-NBI-DGJ), as a novel PC for human mutant beta-Gal. In vitro, 6S-NBI-DGJ had the ability to inhibit the activity of human beta-Gal in a competitive manner and was able to protect this enzyme from heat-induced degradation. Computational analysis supported that the rigid glycone bicyclic core of 6S-NBI-DGJ binds to the active site of the enzyme, with the aglycone N%26apos;-butyl substituent, in a precise E-orientation, located at a hydrophobic region nearby. Chaperone potential profiling indicated significant increases of enzyme activity in 24 of 88 beta-Gal mutants, including four common mutations. Finally, oral administration of 6S-NBI-DGJ amelio-rated the brain pathology of GM(1) gangliosidosis model mice. These results suggest that 6S-NBI-DGJ is a novel PC that may be effective on a broad range of beta-Gal mutants.

• 出版日期2013-3