Development of a new molecular therapeutic drug for brain pathology in lysosomal storage diseases

溶酶体贮积症脑病理学新型分子治疗药物的开发

• 批准号: 14207106
• 负责人: SUZUKI Yoshiyuki
• 金额: $ 31.37万
• 依托单位: International University of Health and Welfare
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14207106/
• 关键词: chemical chaperone therapy; β-galactosidase; G_<M1>-gangliosidosis; competitive inhibitor; genetically engineered mouse; N-octyl-4-epi-β-valianamine; lysosomal disease; β-ガラクトシダーセ; GM1-ガングリオシドーシス

We synthesized a novel galactose derivative, N-octyl-4-epi-β-valienamine(NOEV), for a new molecular therapy (chemical chaperone therapy) of a human neurogenetic disease, β-galactosidosis (G_<M1>-gangliosidosis and Morquio B disease). It has a molecular structure analogous to galactose ; molecular weight is 287.40. It is stable at room temperature, and has limited solubility in water (up to 5 mM), but freely soluble in methanol or dimethylsulfoxide. It is a potent competitive inhibitor of lysosomal (β-galactosidase in vitro. IC50 is 0.2 μM. Addition of NOEV in the culture medium restored mutant enzyme activity in cultured human or murine fibroblasts at low intracellular concentrations, resulting in a marked decrease of intracellular substrate storage. We collected 50 fibroblast strains from β-galactosidase deficiency disorders from all over the world, for testing the NOEV effect in the culture system. More than 3-fold increase was observed in 35% of them. The effect was most prominent in mutations causing juvenile G_<M1>-gangliosidosis, and less effective to those causing infantile or adult G_<M1>-gangliosidosis. So far Morquio B cells did not respond significantly in this assay system. We have established a method of NOEV determination in tissues and blood, and started mouse experiments by oral administration of this compound. Chemical chaperone therapy may be useful for certain patients with β-galactosidosis and potentially other lysosomal storage diseases with central nervous system involvement.

我们合成了新型的半乳糖衍生物，N-辛基-4-β-β-甲胺（NOEV）欧洲遗传疾病，β-半乳糖菌病（G_ <m1> - gan虫病和Morquio B疾病）为287.40。在培养的人或鼠类植物浓度中，从全世界的β-半乳糖苷酶疾病中收集了50个纤维菌株，以测试培养系统中的NOEV效应。 。通过口服该小伙子开始了小鼠实验。

项目成果

Suzuki Y, Oshima A, Nanba E: "Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B(eds):The Metabolic and Molecular Bases of Inherited Disease, 8th ed, Internet Version"β-Galactosidase deficiency(β-galactosidosis):G_<M1>-Gangliosidosis and Morq

Suzuki Y、Oshima A、Nanba E：“Scriver CR、Beaudet AL、Sly WS、Valle D、Childs B、Vogelstein B（编辑）：遗传性疾病的代谢和分子基础，第 8 版，互联网版本”β-半乳糖苷酶缺乏症（β-半乳糖苷沉积症）：G_<M1>-神经节苷脂沉积症和 Morq

Ogawa S, Matsunaga YK, Suzuki Y: "Chemical modification of the β-glucocerebrosidase inhibitor N-octyl-β-valienamine : Synthesis and biological evaluation of 4-epimeric and 4-O-(β-D-galactopyranosyl)derivatives"Bioorganic and Medicinal Chemistry. 10. 1967-

小川 S、松永 YK、铃木 Y：“β-葡萄糖脑苷脂酶抑制剂 N-辛基-β-缬烯胺的化学修饰：4-差向异构体和 4-O-(β-D-吡喃半乳糖基) 衍生物的合成和生物学评价”生物有机和药物化学。 10. 1967-

鈴木義之: "β-ガラクトシドーシス:新しい分子治療法の開発"神経研究の進歩. 46. 851-858 (2002)

Yoshiyuki Suzuki：“β-半乳糖苷沉积症：新分子疗法的发展”神经学研究进展 46. 851-858 (2002)。