Chaperone therapy for neuronopathic lysosomal diseases

Competitive inhibitors as chemical chaperones for enhancement of mutant enzyme activities

Yoshiyuki Suzuki, Seiichiro Ogawa, Yasubumi Sakakibara

Research output: Contribution to journalArticle

83 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)7-19
Number of pages13
JournalPerspectives in Medicinal Chemistry
Volume2009
Issue number3
Publication statusPublished - 2009

Fingerprint

GM1 Gangliosidosis
Galactosidases
Enzymes
Gaucher Disease
Glucosidases
Therapeutics
Carbasugars
Lysosomal Storage Diseases
Inborn Genetic Diseases
valienamine
Glycoside Hydrolases
Medical Genetics
Brain
Blood-Brain Barrier
Central Nervous System
Fibroblasts
Mutation
Research
Genes

Keywords

  • β-galactosidase
  • β-glucosidase
  • Chaperone
  • G-gangliosidosis
  • Gaucher disease
  • Lysosomal disease
  • Lysosomal enzyme
  • Valienamine

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmaceutical Science
  • Pharmacology
  • Pharmacology (medical)

Cite this

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abstract = "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.",
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