A counterintuitive approach to treat enzyme deficiencies: use of enzyme inhibitors for restoring mutant enzyme activity
-
Jian-Qiang Fan
Abstract
Pharmacological chaperone therapy is an emerging counterintuitive approach to treat protein deficiencies resulting from mutations causing misfolded protein conformations. Active-site-specific chaperones (ASSCs) are enzyme active-site directed small molecule pharmacological chaperones that act as a folding template to assist protein folding of mutant proteins in the endoplasmic reticulum (ER). As a result, excessive degradation of mutant proteins in the ER-associated degradation (ERAD) machinery can be prevented, thus restoring enzyme activity. Lysosomal storage disorders (LSDs) are suitable candidates for ASSC treatment, as the levels of enzyme activity needed to prevent substrate storage are relatively low. In addition, ASSCs are orally active small molecules and have potential to gain access to most cell types to treat neuronopathic LSDs. Competitive enzyme inhibitors are effective ASSCs when they are used at sub-inhibitory concentrations. This whole new paradigm provides excellent opportunity for identifying specific drugs to treat a broad range of inherited disorders. This review describes protein misfolding as a pathophysiological cause in LSDs and provides an overview of recent advances in the development of pharmacological chaperone therapy for the diseases. In addition, a generalized guidance for the design and screening of ASSCs is also presented.
©2008 by Walter de Gruyter Berlin New York
Articles in the same Issue
- A counterintuitive approach to treat enzyme deficiencies: use of enzyme inhibitors for restoring mutant enzyme activity
- Reassessing the role of a 3′-UTR-binding translational inhibitor in regulation of circadian bioluminescence rhythm in the dinoflagellate Gonyaulax
- Cloning, functional analysis, and mitochondrial localization of Trypanosoma brucei monothiol glutaredoxin-1
- A new subfamily of bacterial glutamate/aspartate receptors
- Synthesis and characterization of a functional intact IgG in a prokaryotic cell-free expression system
- Collagen IV regulates Caco-2 cell spreading and p130Cas phosphorylation by FAK-dependent and FAK-independent pathways
- Differential effects of novel tumour-derived p53 mutations on the transformation of NIH-3T3 cells
- Employing Rhodobacter sphaeroides to functionally express and purify human G protein-coupled receptors
- Heparinase selectively sheds heparan sulphate from the endothelial glycocalyx
- Inhibition of human μ-calpain by conformationally constrained calpastatin peptides
- Cloning, expression and characterization of insulin-degrading enzyme from tomato (Solanum lycopersicum)
Articles in the same Issue
- A counterintuitive approach to treat enzyme deficiencies: use of enzyme inhibitors for restoring mutant enzyme activity
- Reassessing the role of a 3′-UTR-binding translational inhibitor in regulation of circadian bioluminescence rhythm in the dinoflagellate Gonyaulax
- Cloning, functional analysis, and mitochondrial localization of Trypanosoma brucei monothiol glutaredoxin-1
- A new subfamily of bacterial glutamate/aspartate receptors
- Synthesis and characterization of a functional intact IgG in a prokaryotic cell-free expression system
- Collagen IV regulates Caco-2 cell spreading and p130Cas phosphorylation by FAK-dependent and FAK-independent pathways
- Differential effects of novel tumour-derived p53 mutations on the transformation of NIH-3T3 cells
- Employing Rhodobacter sphaeroides to functionally express and purify human G protein-coupled receptors
- Heparinase selectively sheds heparan sulphate from the endothelial glycocalyx
- Inhibition of human μ-calpain by conformationally constrained calpastatin peptides
- Cloning, expression and characterization of insulin-degrading enzyme from tomato (Solanum lycopersicum)
