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

Yoshiyuki Suzuki,Yasubumi Sakakibara,Seiichiro Ogawa

doi:10.4137/pmc.s2332

Yoshiyuki Suzuki, Yasubumi Sakakibara + Show 1 more

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https://doi.org/10.4137/pmc.s2332

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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-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.

Highlights

Lysosome is one of the cellular organelles where various high molecular endogenous or exogenous compounds are systematically digested under the acidic condition.[1]
After our early studies on galactose and 1-deoxygalactonojirimycin (DGJ), we developed new valienamine derivatives, N-octyl-4-epi-βvalienamine (NOEV) and N-octyl-β-valienamine (NOV) as chemical chaperones for mutant β-galactosidase and β-glucosidase proteins, respectively, to restore the enzyme activity in somatic cells from patients with GM1-gangliosidosis and Gaucher disease.[14,15,16]
In this article we summarize our experimental results of chaperone effect and chaperone therapy mainly on NOEV for GM1-gangliosidosis

Summary

Introduction

Lysosome is one of the cellular organelles where various high molecular endogenous or exogenous compounds are systematically digested under the acidic condition.[1]. Perspectives in Medicinal Chemistry 2009:3 7–19 competitive inhibitors could serve as chemical chaperones to induce expression of catalytic activities of mutant enzymes after stabilization and successful intracellular transport to the lysosome in the cells We reported this enhancement first in Fabry disease,[12,13] and in GM1-gangliosidosis[14] and Gaucher disease.[15]. After our early studies on galactose and 1-deoxygalactonojirimycin (DGJ), we developed new valienamine derivatives, N-octyl-4-epi-βvalienamine (NOEV) and N-octyl-β-valienamine (NOV) as chemical chaperones for mutant β-galactosidase and β-glucosidase proteins, respectively, to restore the enzyme activity in somatic cells from patients with GM1-gangliosidosis and Gaucher disease.[14,15,16] We hope that this phenomenon will be applied to development of novel molecular therapeutic approach to lysosomal diseases, with severe brain damage, in the near future.

15 Carbaglucosylceramide

Findings

Conclusion