Pharmacological Chaperones as Therapeutics for Lysosomal Storage Diseases

Lysosomal enzymes are responsible for the degradation of a wide variety of glycolipids, oligosaccharides, proteins, and glycoproteins. Inherited mutations in the genes that encode these proteins can lead to reduced stability of newly synthesized lysosomal enzymes. While often catalytically competent...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2013-04, Vol.56 (7), p.2705-2725
Main Authors: Boyd, Robert E, Lee, Gary, Rybczynski, Philip, Benjamin, Elfrida R, Khanna, Richie, Wustman, Brandon A, Valenzano, Kenneth J
Format: Article
Language:English
Subjects:
Cell Line
Glycolipids - metabolism
Humans
Lysosomal Storage Diseases - drug therapy
Molecular Chaperones - therapeutic use
Structure-Activity Relationship
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Summary:Lysosomal enzymes are responsible for the degradation of a wide variety of glycolipids, oligosaccharides, proteins, and glycoproteins. Inherited mutations in the genes that encode these proteins can lead to reduced stability of newly synthesized lysosomal enzymes. While often catalytically competent, the mutated enzymes are unable to efficiently pass the quality control mechanisms of the endoplasmic reticulum, resulting in reduced lysosomal trafficking, substrate accumulation, and cellular dysfunction. Pharmacological chaperones (PCs) are small molecules that bind and stabilize mutant lysosomal enzymes, thereby allowing proper cellular translocation. Such compounds have been shown to increase enzyme activity and reduce substrate burden in a number of preclinical models and clinical studies. In this Perspective, we review several of the lysosomal diseases for which PCs have been studied and the SAR of the various classes of molecules.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm301557k