Pan Yuchen, Doherty Gareth G, Al Nahain Abdullah, Wimmer Norbert, Lau Adeline A, Hemsley Kim M, Ferro Vito
School of Chemistry & Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
Childhood Dementia Research Group, College of Medicine and Public Health, Flinders Health and Medical Research Institute (FHMRI), Flinders University, Bedford Park, SA, 5042, Australia.
Org Biomol Chem. 2025 Jul 2;23(26):6446-6455. doi: 10.1039/d5ob00699f.
Sanfilippo syndrome (Mucopolysaccharidosis type III, or MPS III) is an inherited neurodegenerative disorder resulting from mutations in genes encoding lysosomal enzymes that sequentially degrade heparan sulfate. Currently, there are no approved treatments and life expectancy is <20 years. The two most common subtypes are MPS IIIA and IIIB, caused by mutations in -sulfoglucosamine sulfohydrolase (SGSH) and α--acetylglucosaminidase (NAGLU), respectively. Fluorogenic substrates based on a 4-methylumbelliferyl aglycone for both SGSH and NAGLU are critical components of cell-based assays used in drug screening efforts for MPS IIIA and IIIB. However, the reported syntheses suffer from low yields due to poor α-selectivity in the key aromatic glycosylation step. Herein we report new, efficient syntheses of both substrates featuring a completely α-selective glycosylation the use of a thioglycoside donor pre-activated with diphenyl sulfoxide/triflic anhydride. We also demonstrate the utility of these substrates for quantitating SGSH and NAGLU activity in tissues from MPS IIIA or IIIB mice.
桑菲利波综合征（粘多糖贮积症III型，或MPS III）是一种遗传性神经退行性疾病，由编码溶酶体酶的基因突变引起，这些酶依次降解硫酸乙酰肝素。目前，尚无获批的治疗方法，预期寿命小于20岁。两种最常见的亚型是MPS IIIA和IIIB，分别由硫酸氨基葡萄糖硫酸酯酶（SGSH）和α-N-乙酰氨基葡萄糖苷酶（NAGLU）的突变引起。基于4-甲基伞形酮苷元的用于SGSH和NAGLU的荧光底物是用于MPS IIIA和IIIB药物筛选的基于细胞的检测的关键组成部分。然而，由于关键的芳香族糖基化步骤中α-选择性差，报道的合成方法产率较低。在此，我们报道了两种底物的新型高效合成方法，其具有完全的α-选择性糖基化——使用用二苯基亚砜/三氟甲磺酸酐预活化的硫代糖苷供体。我们还证明了这些底物在定量来自MPS IIIA或IIIB小鼠组织中SGSH和NAGLU活性方面的实用性。
