Molecular Basis of 1‑Deoxygalactonojirimycin Arylthiourea Binding to Human α‑Galactosidase A: Pharmacological Chaperoning Efficacy on Fabry Disease Mutants

• Published in: ACS chemical biology 2014-07, Vol.9 (7), p.1460-1469
• Main Authors: Yu, Yi, Mena-Barragán, Teresa, Higaki, Katsumi, Johnson, Jennifer L, Drury, Jason E, Lieberman, Raquel L, Nakasone, Naoe, Ninomiya, Haruaki, Tsukimura, Takahiro, Sakuraba, Hitoshi, Suzuki, Yoshiyuki, Nanba, Eiji, Mellet, Carmen Ortiz, García Fernández, José M, Ohno, Kousaku
• Format: Article
• Language: English
• Subjects: 1-Deoxynojirimycin - analogs & derivatives; 1-Deoxynojirimycin - chemistry; 1-Deoxynojirimycin - pharmacology; alpha-Galactosidase - chemistry; alpha-Galactosidase - genetics; alpha-Galactosidase - metabolism; Animals; Autophagy - drug effects; Cercopithecus aethiops; COS Cells; Crystallography, X-Ray; Enzyme Stability - drug effects; Fabry Disease - drug therapy; Fabry Disease - enzymology; Fabry Disease - genetics; Fabry Disease - pathology; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Humans; Molecular Docking Simulation; Mutation; Protein Transport - drug effects; Thiourea - analogs & derivatives; Thiourea - pharmacology; Trihexosylceramides - metabolism
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/cb500143h

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.