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Discovery of a novel noniminosugar acid α glucosidase chaperone series.

Discovery of a novel noniminosugar acid α glucosidase chaperone series.

Authors :
Xiao J
Westbroek W
Motabar O
Lea WA
Hu X
Velayati A
Zheng W
Southall N
Gustafson AM
Goldin E
Sidransky E
Liu K
Simeonov A
Tamargo RJ
Ribes A
Matalonga L
Ferrer M
Marugan JJ
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.

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