An injectable hydrogel containing N-acetylglycine for the treatment of Gaucher disease
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View abstract on PubMed
Summary
This summary is machine-generated.N-acetylglycine (NAG) effectively stabilizes the glucocerebrosidase (GCase) enzyme, offering a promising treatment for Gaucher disease (GD). This small molecule stabilizer was identified through computational screening and validated in preclinical models, improving GCase activity and patient outcomes.
Area Of Science
- Biochemistry and Genetics
- Pharmacology and Drug Discovery
- Computational Biology
Background
- Gaucher disease (GD) is a rare inherited lysosomal storage disorder caused by mutations in the GBA1 gene, leading to deficient glucocerebrosidase (GCase) enzyme activity and glycolipid accumulation.
- Small-molecule protein stabilizers represent a promising therapeutic strategy for genetic disorders by restoring mutant protein function.
- Developing novel GCase stabilizers is challenging due to the high cost and time associated with traditional in vitro and in vivo studies.
Purpose Of The Study
- To develop a comprehensive preclinical process pipeline for identifying novel GCase stabilizers for Gaucher disease treatment.
- To screen existing small molecules for their potential to stabilize mutant GCase using computational and experimental methods.
- To evaluate the therapeutic efficacy of the lead stabilizer, N-acetylglycine (NAG), in preclinical models of Gaucher disease.
Main Methods
- A stepwise funnel selection approach was employed, starting with high-throughput molecular docking to screen small molecules.
- Top candidates, N-acetylglycine (NAG) and deoxycholic acid (DCA), were further analyzed using molecular dynamics simulations and binding free energy calculations.
- In vitro and in vivo toxicity studies, cell-based assays (chemical and siRNA knockdown), and a Gaucher mouse model (CBE-induced) were utilized for efficacy evaluation.
Main Results
- Molecular docking identified NAG and DCA as potential GCase stabilizers; subsequent simulations confirmed their stabilizing potential.
- NAG demonstrated significant GCase activity enhancement in GD cell models and improved motor behavior in a Gaucher mouse model.
- An injectable hydrogel formulation of NAG was successfully developed and showed efficacy in treating GD and improving survival in preclinical studies.
Conclusions
- The developed process pipeline efficiently identified N-acetylglycine (NAG) as a potent small-molecule stabilizer for the GCase enzyme.
- NAG exhibits therapeutic potential for Gaucher disease by restoring GCase activity and ameliorating disease phenotypes in preclinical models.
- Injectable hydrogel formulation offers a promising drug delivery strategy for NAG in the treatment of Gaucher disease.
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