Chaperone Therapy for Neuronopathic Lysosomal Diseases: Competitive Inhibitors as Chemical Chaperones for Enhancement of Mutant Enzyme Activities

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.

Identification and Characterization of Pharmacological Chaperones to Correct Enzyme Deficiencies in Lysosomal Storage Disorders

“…For instance, 1%-2% of normal a-iduronidase activity has been reported in mild cases of MPS I 145 ; < 1% of normal GCase activity has been reported in mild Gaucher disease 146 ; 6% of normal b-galactosidase activity has been reported in late-onset GM1 gangliosidosis 147 ; 2-4% of normal b-hexosaminidase activity has been reported in the adult form of GM2 gangliosidosis 148 ; and 10% of normal enzyme activity seems to prevent GM1 and GM2 gangliosidoses altogether. 147,149,150 Further, healthy individuals who are carriers of arylsulfatase A 151-153 or b-hexosaminidase deficiency 154,155 have been identified with extremely low residual enzyme activities that are typically seen in severely affected patients. These data suggest that small increases in activity could have a significant impact on substrate levels, and hence disease severity and the rate of disease progression.…”

Fluorous iminoalditols act as effective pharmacological chaperones against gene products from GLB1 alleles causing GM1‐gangliosidosis and Morquio B disease

“…Derivatives of 1-deoxygalactonojirimycin (DGJ, Amigal™) and 1-deoxynojirimycin (DNJ), for example, have been proposed for EET (Asano 2003;Fan 2008) and tested in clinical trials for Fabry disease (Benjamin et al 2009;Khanna et al 2010). Furthermore, a pharmacological chaperone acting on β-gal from GM1 cells, N-octyl-4-epi-beta-valienamine (NOEV), is currently evaluated in pre-clinical tests (Suzuki 2008;Suzuki et al 2009). …”

Biosynthesis and Biological Activity of Carbasugars

“…These activities suggest that carbasugar derivatives 165 and 166 work as chemical chaperones [112,[336][337][338] to accelerate transport and maturation of mutant forms of enzyme proteins and therefore may be useful for certain patients with -galactosidosis and potentially other lysosomal storage diseases [339][340][341][342][343][344][345][346][347][348][349][350][351]. It should be opportune at this point to clarify the concept of chemical chaperone [352][353][354].…”