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

[fabry disease]

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 D 231 of α-Gal A , as confirmed by a 2 .55 Å resolution cocrystal structure . Selected candidates enhanced α-Gal A activity and ameliorate globotriaosylceramide (Gb 3 ) 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 .