Chaperone effect of sulfated disaccharide from heparin on mutant iduronate-2-sulfatase in mucopolysaccharidosis type II

• Published in: Molecular genetics and metabolism 2018-02, Vol.123 (2), p.118-122
• Main Authors: Hoshina, Hiroo, Shimada, Yohta, Higuchi, Takashi, Kobayashi, Hiroshi, Ida, Hiroyuki, Ohashi, Toya
• Format: Article
• Language: English
• Subjects: Disaccharides - pharmacology; Fibroblasts - drug effects; Fibroblasts - enzymology; Fibroblasts - pathology; Gene Expression Regulation, Enzymologic - drug effects; Glycosaminoglycans - metabolism; HEK293 Cells; Heparin - chemistry; Humans; Iduronate Sulfatase - genetics; Iduronate Sulfatase - metabolism; Iduronic Acid - metabolism; Molecular Chaperones; MPS II; Mucopolysaccharidosis II - drug therapy; Mucopolysaccharidosis II - enzymology; Mucopolysaccharidosis II - genetics; Mucopolysaccharidosis type II; Mutation; Pharmacological chaperone; Skin - drug effects; Skin - enzymology; Skin - pathology; Sulfated disaccharide; Sulfates - chemistry
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2017.12.428

Small molecules called pharmacological chaperones have been shown to improve the stability, intracellular localization, and function of mutated enzymes in several lysosomal storage diseases, and proposed as promising therapeutic agents for them. However, a chaperone compound for mucopolysaccharidosis type II (MPS II), which is an X-linked lysosomal storage disorder characterized by a deficiency of iduronate-2-sulfatase (IDS) and the accumulation of glycosaminoglycans (GAGs), has still not been developed. Here we focused on the Δ-unsaturated 2-sulfouronic acid-N-sulfoglucosamine (D2S0), which is a sulfated disaccharide derived from heparin, as a candidate compound for a pharmacological chaperone for MPS II, and analyzed the chaperone effect of the saccharide on IDS by using recombinant protein and cells expressing mutated enzyme. When D2S0 was incubated with recombinant human IDS (rhIDS) in vitro, the disaccharide attenuated the thermal degeneration of the enzyme. This effect of D2S0 on the thermal degeneration of rhIDS was enhanced in a dose-dependent manner. D2S0 also increased the residual activity of mutant IDS in patient fibroblasts. Furthermore, D2S0 improved the enzyme activity of IDS mutants derived from six out of seven different mutations in HEK293T cells transiently expressing them. These results indicate that D2S0 is a potential pharmacological chaperone for MPS II. •Δ-unsaturated 2-sulfouronic acid-N-sulfoglucosamine (D2S0) binds to recombinant human IDS (rhIDS).•D2S0 increases the thermal stability of rhIDS in vitro.•D2S0 improves the enzymatic activity of mutated IDS in cultured cells.