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Discovery of a novel noniminosugar acid α glucosidase chaperone series.
Discovery of a novel noniminosugar acid α glucosidase chaperone series.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2012 Sep 13; Vol. 55 (17), pp. 7546-59. Date of Electronic Publication: 2012 Aug 17. - Publication Year :
- 2012
-
Abstract
- Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the lysosomal enzyme acid α-glucosidase (GAA). Many disease-causing mutated GAA retain enzymatic activity but are not translocated from endoplasmic reticulum (ER) to lysosomes. Enzyme replacement therapy (ERT) is the only treatment for Pompe disease but remains expensive, inconvenient, and does not reverse all disease manifestations. It was postulated that small molecules which aid in protein folding and translocation to lysosomes could provide an alternate to ERT. Previously, several iminosugars have been proposed as small-molecule chaperones for specific LSDs. Here we identified a novel series of noniminosugar chaperones for GAA. These moderate GAA inhibitors are shown to bind and thermostabilize GAA and increase GAA translocation to lysosomes in both wild-type and Pompe fibroblasts. AMDE and physical properties studies indicate that this series is a promising lead for further pharmacokinetic evaluation and testing in Pompe disease models.
- Subjects :
- Blotting, Western
Cells, Cultured
Enzyme Replacement Therapy
Glycogen Storage Disease Type II drug therapy
Humans
Immunohistochemistry
Magnetic Resonance Spectroscopy
Microscopy, Confocal
Small Molecule Libraries
Spectrometry, Mass, Electrospray Ionization
Structure-Activity Relationship
alpha-Glucosidases pharmacology
alpha-Glucosidases therapeutic use
Drug Discovery
Imino Sugars chemistry
Molecular Chaperones
alpha-Glucosidases chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 55
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22834902
- Full Text :
- https://doi.org/10.1021/jm3005543