Candidate Molecules for Chemical Chaperone Therapy of G
            <sub>M1</sub>
            -Gangliosidosis

Higaki, Kazutaka; Ninomiya, Haruaki; Suzuki, Yoshiyuki; Nanba, Eiji

doi:10.4155/fmc.13.123

Cited by 16 publications

(13 citation statements)

References 77 publications

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“…Pharmacological chaperones were originally designed as competitive inhibitors of β-gal, promoting proper folding and stabilizing the enzyme in its active state for safe transport to the lysosome. 91,93,[178][179][180] Unstable mutant enzymes in the absence of PCs are rapidly processed by ER-associated protein degradation. In some cases, misfolding and aggregation of mutant β-gal leads to ER stress, the UPR, and apoptosis.…”

Section: Pharmacological Chaperonesmentioning

confidence: 99%

GM1 Gangliosidosis: Mechanisms and Management

Rha¹,

Maguire²,

Martin³

2021

TACG

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The lysosomal storage disorder, GM1 gangliosidosis (GM1), is a neurodegenerative condition resulting from deficiency of the enzyme β-galactosidase (β-gal). Mutation of the GLB1 gene, which codes for β-gal, prevents cleavage of the terminal β-1,4-linked galactose residue from GM1 ganglioside. Subsequent accumulation of GM1 ganglioside and other substrates in the lysosome impairs cell physiology and precipitates dysfunction of the nervous system. Beyond palliative and supportive care, no FDA-approved treatments exist for GM1 patients. Researchers are critically evaluating the efficacy of substrate reduction therapy, pharmacological chaperones, enzyme replacement therapy, stem cell transplantation, and gene therapy for GM1. A Phase I/II clinical trial for GM1 children is ongoing to evaluate the safety and efficacy of adeno-associated virus-mediated GLB1 delivery by intravenous injection, providing patients and families with hope for the future.

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Section: Pharmacological Chaperonesmentioning

confidence: 99%

GM1 Gangliosidosis: Mechanisms and Management

Rha¹,

Maguire²,

Martin³

2021

TACG

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“…19,26) Chaperone therapy is theoretically effective in 30–60% of patients with Fabry disease and G M1 -gangliosidosis patients. 28,29) …”

Section: Theoretical Background Of Chaperone Therapymentioning

confidence: 99%

“…29,47) Thus, the combination of NOEV and MTD118 will cover 60–70% of patients with G M1 -gangliosidosis, and hopefully those with Morquio B disease. Galactose was reported to be a potential chemical chaperone in some G M1 -gangliosidosis mutations as well as in Fabry disease.…”

Section: Chaperone Therapy For Lysosomal Diseasesmentioning

confidence: 99%

Emerging novel concept of chaperone therapies for protein misfolding diseases

Suzuki

2014

Proceedings of the Japan Academy. Ser. B: Physical and Biologic

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Chaperone therapy is a newly developed molecular therapeutic approach to protein misfolding diseases. Among them we found unstable mutant enzyme proteins in a few lysosomal diseases, resulting in rapid intracellular degradation and loss of function. Active-site binding low molecular competitive inhibitors (chemical chaperones) paradoxically stabilized and enhanced the enzyme activity in somatic cells by correction of the misfolding of enzyme protein. They reached the brain through the blood-brain barrier after oral administration, and corrected pathophysiology of the disease. In addition to these inhibitory chaperones, non-competitive chaperones without inhibitory bioactivity are being developed. Furthermore molecular chaperone therapy utilizing the heat shock protein and other chaperone proteins induced by small molecules has been experimentally tried to handle abnormally accumulated proteins as a new approach particularly to neurodegenerative diseases. These three types of chaperones are promising candidates for various types of diseases, genetic or non-genetic, and neurological or non-neurological, in addition to lysosomal diseases.

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“…It can control blood glucose elevation, and various diseases caused by hyperglycemia, such as diabetes. In addition, it can effectively treat sclerosis, obesity, diabetes, and hyperlipidemia [2,3]. According to the specificity of chiral carbon atoms, valienamine has two isomers in its natural condition: valienamine and β-valienamine.…”

Section: Introductionmentioning

confidence: 99%

Exploration of Catalytic Selectivity for Aminotransferase (BtrR) Based on Multiple Molecular Dynamics Simulations

Liu

Wan

Zhu

et al. 2019

IJMS

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The aminotransferase from Bacillus circulans (BtrR), which is involved in the biosynthesis of butirosin, catalyzes the pyridoxal phosphate (PLP)-dependent transamination reaction to convert valienone to β-valienamine (a new β-glycosidase inhibitor for the treatment of lysosomal storage diseases) with an optical purity enantiomeric excess value. To explore the stereoselective mechanism of valienamine generated by BtrR, multiple molecular dynamics (MD) simulations were performed for the BtrR/PLP/valienamine and BtrR/PLP/β-valienamine complexes. The theoretical results showed that β-valienamine could make BtrR more stable and dense than valienamine. β-valienamine could increase the hydrogen bond probability and decrease the binding free energy between coenzyme PLP and BtrR by regulating the protein structure of BtrR, which was conducive to the catalytic reaction. β-valienamine maintained the formation of cation-p interactions between basic and aromatic amino acids in BtrR, thus enhancing its stability and catalytic activity. In addition, CAVER 3.0 analysis revealed that β-valienamine could make the tunnel of BtrR wider and straight, which was propitious to the removal of products from BtrR. Steered MD simulation results showed that valienamine interacted with more residues in the tunnel during dissociation compared with β-valienamine, resulting in the need for a stronger force to be acquired from BtrR. Taken together, BtrR was more inclined to catalyze the substrates to form β-valienamine, either from the point of view of the catalytic reaction or product removal.

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Candidate Molecules for Chemical Chaperone Therapy of G _M1 -Gangliosidosis

Cited by 16 publications

References 77 publications

GM1 Gangliosidosis: Mechanisms and Management

GM1 Gangliosidosis: Mechanisms and Management

Emerging novel concept of chaperone therapies for protein misfolding diseases

Exploration of Catalytic Selectivity for Aminotransferase (BtrR) Based on Multiple Molecular Dynamics Simulations

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Candidate Molecules for Chemical Chaperone Therapy of G M1 -Gangliosidosis

Cited by 16 publications

References 77 publications

GM1 Gangliosidosis: Mechanisms and Management

GM1 Gangliosidosis: Mechanisms and Management

Emerging novel concept of chaperone therapies for protein misfolding diseases

Exploration of Catalytic Selectivity for Aminotransferase (BtrR) Based on Multiple Molecular Dynamics Simulations

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Candidate Molecules for Chemical Chaperone Therapy of G _M1 -Gangliosidosis