Molecular basis of 1-deoxygalactonojirimycin arylthiourea binding to human α-galactosidase a: pharmacological chaperoning efficacy on Fabry disease mutants.

TitleMolecular basis of 1-deoxygalactonojirimycin arylthiourea binding to human α-galactosidase a: pharmacological chaperoning efficacy on Fabry disease mutants.
Publication TypeJournal Article
Year of Publication2014
AuthorsYu Y, Mena-Barragán T, Higaki K, Johnson JL, Drury JE, Lieberman RL, Nakasone N, Ninomiya H, Tsukimura T, Sakuraba H, Suzuki Y, Nanba E, Mellet CO, García Fernández JM, Ohno K
JournalACS chemical biology
Volume9
Issue7
Pagination1460-9
Date Published2014 Jul 18
ISSN1554-8937
Abstract

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene often leading to missense α-galactosidase A (α-Gal A) variants that undergo premature endoplasmic reticulum-associated degradation due to folding defects. We have synthesized and characterized a new family of neutral amphiphilic pharmacological chaperones, namely 1-deoxygalactonojirimycin-arylthioureas (DGJ-ArTs), capable of stabilizing α-Gal A and restoring trafficking. Binding to the enzyme is reinforced by a strong hydrogen bond involving the aryl-N'H thiourea proton and the catalytic aspartic acid acid D231 of α-Gal A, as confirmed by a 2.55 Å resolution cocrystal structure. Selected candidates enhanced α-Gal A activity and ameliorate globotriaosylceramide (Gb3) accumulation and autophagy impairments in FD cell cultures. Moreover, they acted synergistically with the proteostasis regulator 4-phenylbutyric acid, appearing to be promising leads as pharmacological chaperones for FD.

DOI10.1021/cb500143h
Alternate JournalACS Chem. Biol.