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-beta-valienamine (NOEV) and
N-octyl-beta-valienamine (NOV), as promising therapeutic agents for human
beta-galactosidase deficiency disorders (mainly G(M1)-gangliosidosis) and
beta-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 G(M1)-gangliosidosis model mice were developed and useful for experimental studies. Orally administered NOEV entered the brain through the blood-brain barrier, enhanced
beta-galactosidase activity, reduced substrate storage, and improved neurological deterioration clinically. Furthermore, we executed computational analysis for prediction of molecular interactions between
beta-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
beta-glucosidase gene mutations in
Gaucher disease. We hope chaperone
therapy will become available for some patients with G(M1)-gangliosidosis,
Gaucher disease, and potentially other
lysosomal storage diseases with central nervous system involvement.