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 language | English |
|---|---|
| Pages (from-to) | 7-19 |
| Number of pages | 13 |
| Journal | Perspectives in Medicinal Chemistry |
| Volume | 2009 |
| Issue number | 3 |
| Publication status | Published - 2009 |
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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
Chaperone therapy for neuronopathic lysosomal diseases : Competitive inhibitors as chemical chaperones for enhancement of mutant enzyme activities. / Suzuki, Yoshiyuki; Ogawa, Seiichiro; Sakakibara, Yasubumi.
In: Perspectives in Medicinal Chemistry, Vol. 2009, No. 3, 2009, p. 7-19.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Chaperone therapy for neuronopathic lysosomal diseases
T2 - Competitive inhibitors as chemical chaperones for enhancement of mutant enzyme activities
AU - Suzuki, Yoshiyuki
AU - Ogawa, Seiichiro
AU - Sakakibara, Yasubumi
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
KW - β-galactosidase
KW - β-glucosidase
KW - Chaperone
KW - G-gangliosidosis
KW - Gaucher disease
KW - Lysosomal disease
KW - Lysosomal enzyme
KW - Valienamine
UR - http://www.scopus.com/inward/record.url?scp=77953386183&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77953386183&partnerID=8YFLogxK
M3 - Article
AN - SCOPUS:77953386183
VL - 2009
SP - 7
EP - 19
JO - Perspectives in Medicinal Chemistry
JF - Perspectives in Medicinal Chemistry
SN - 1177-3910
IS - 3
ER -