ArticlePerspectives in medicinal chemistry2009
Chaperone therapy for neuronopathic lysosomal diseases: competitive inhibitors as chemical chaperones for enhancement of mutant enzyme activities.
Article in Perspectives in medicinal chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30 citing papers in PubMed, 67 citations in OpenAlex.
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- Hematopoietic stem cell gene therapy ameliorates CNS involvement in murine model of GM1-gangliosidosis.Molecular therapy. Methods & clinical development · 2022Article
- Design and synthesis of biologically active carbaglycosylamines: From glycosidase inhibitors to pharmacological chaperones.Proceedings of the Japan Academy. Series B, Physical and biological sciences · 2022Review
- GM1 Gangliosidosis: Mechanisms and Management.The application of clinical genetics · 2021Review
- Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes andMolecules (Basel, Switzerland) · 2020Article
- Novel stereoselective syntheses ofRSC advances · 2019Article
- Exploration of Catalytic Selectivity for Aminotransferase (BtrR) Based on Multiple Molecular Dynamics Simulations.International journal of molecular sciences · 2019Article
- Induced Pluripotent Stem Cell Modeling of Gaucher's Disease: What Have We Learned?International journal of molecular sciences · 2017Review
- New therapeutic approaches for Krabbe disease: The potential of pharmacological chaperones.Journal of neuroscience research · 2016Review
- The relationship between glucocerebrosidase mutations and Parkinson disease.Journal of neurochemistry · 2016Review
- From structural biology to designing therapy for inborn errors of metabolism.Journal of inherited metabolic disease · 2016Review
- Heat shock proteins: a therapeutic target worth to consider.Veterinary world · 2015Review
- Chaperone therapy for GM2 gangliosidosis: effects of pyrimethamine on β-hexosaminidase activity in Sandhoff fibroblasts.Molecular neurobiology · 2014Review
- The development and use of small molecule inhibitors of glycosphingolipid metabolism for lysosomal storage diseases.Journal of lipid research · 2014Review
- Structural basis of pharmacological chaperoning for human β-galactosidase.The Journal of biological chemistry · 2014Article
- Emerging novel concept of chaperone therapies for protein misfolding diseases.Proceedings of the Japan Academy. Series B, Physical and biological sciences · 2014Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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