Chaperone therapy for neuronopathic lysosomal diseases: Competitive inhibitors as chemical chaperones for enhancement of mutant enzyme activities

Yoshiyuki Suzuki, Seiichiro Ogawa, Yasubumi Sakakibara

研究成果: Review article査読

88 被引用数 (Scopus)

抄録

Chaperone therapy is a newly developed molecular approach to lysosomal diseases, a group of human genetic diseases causing severe brain damage. We found two valienamine derivatives, N-octyl-4-epi-β-valienamine (NOEV) and N-octyl-β-valienamine (NOV), as promising therapeutic agents for human β-galactosidase deficiency disorders (mainly GM1-gangliosidosis) and β-glucosidase deficiency disorders (Gaucher disease), respectively. We briefly reviewed the historical background of research in carbasugar glycosidase inhibitors. Originally NOEV and NOV had been discovered as competitive inhibitors, and then their paradoxical bioactivities as chaperones were confirmed in cultured fibroblasts from patients with these disorders. Subsequently GM1-gangliosidosis model mice were developed and useful for experimental studies. Orally administered NOEV entered the brain through the blood-brain barrier, enhanced β-galactosidase activity, reduced substrate storage, and improved neurological deterioration clinically. Furthermore, we executed computational analysis for prediction of molecular interactions between β-galactosidase and NOEV. Some preliminary results of computational analysis of molecular interaction mechanism are presented in this article. NOV also showed the chaperone effect toward several β-glucosidase gene mutations in Gaucher disease. We hope chaperone therapy will become available for some patients with GM1-gangliosidosis, Gaucher disease, and potentially other lysosomal storage diseases with central nervous system involvement.

本文言語English
ページ(範囲)7-19
ページ数13
ジャーナルPerspectives in Medicinal Chemistry
2009
3
DOI
出版ステータスPublished - 2009

ASJC Scopus subject areas

  • 薬理学
  • 薬科学
  • 創薬
  • 薬理学(医学)

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