Second-Generation Pharmacological Chaperones: Beyond Inhibitors

被引:37
|
作者
Tran, My Lan [1 ]
Genisson, Yves [1 ]
Ballereau, Stephanie [1 ]
Dehoux, Cecile [1 ]
机构
[1] Univ Paul Sabatier Toulouse III, CNRS, SPCMIB, UMR5068, 118 Route Narbonne, F-31062 Toulouse, France
来源
MOLECULES | 2020年 / 25卷 / 14期
关键词
pharmacological chaperones; lysosomal storage disease; allosteric ligand; conformational disease; non-inhibitory chaperones; LYSOSOMAL STORAGE DISORDERS; ALPHA-GLUCOSIDASE ACTIVITY; PHENYLALANINE-HYDROXYLASE REVEALS; GAUCHER-DISEASE; BETA-GLUCOCEREBROSIDASE; KRABBE DISEASE; POMPE DISEASE; THERAPEUTIC STRATEGIES; POTENTIAL TREATMENT; CRYSTAL-STRUCTURE;
D O I
10.3390/molecules25143145
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Protein misfolding induced by missense mutations is the source of hundreds of conformational diseases. The cell quality control may eliminate nascent misfolded proteins, such as enzymes, and a pathological loss-of-function may result from their early degradation. Since the proof of concept in the 2000s, the bioinspired pharmacological chaperone therapy became a relevant low-molecular-weight compound strategy against conformational diseases. The first-generation pharmacological chaperones were competitive inhibitors of mutant enzymes. Counterintuitively, in binding to the active site, these inhibitors stabilize the proper folding of the mutated protein and partially rescue its cellular function. The main limitation of the first-generation pharmacological chaperones lies in the balance between enzyme activity enhancement and inhibition. Recent research efforts were directed towards the development of promising second-generation pharmacological chaperones. These non-inhibitory ligands, targeting previously unknown binding pockets, limit the risk of adverse enzymatic inhibition. Their pharmacophore identification is however challenging and likely requires a massive screening-based approach. This review focuses on second-generation chaperones designed to restore the cellular activity of misfolded enzymes. It intends to highlight, for a selected set of rare inherited metabolic disorders, the strategies implemented to identify and develop these pharmacologically relevant small organic molecules as potential drug candidates.
引用
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页数:21
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