Identification of an Allosteric Binding Site on Human Lysosomal Alpha-Galactosidase Opens the Way to New Pharmacological Chaperones for Fabry Disease

• Published in: PloS one Vol. 11; no. 10; p. e0165463
• Main Authors: Citro, Valentina, Peña-García, Jorge, den-Haan, Helena, Pérez-Sánchez, Horacio, Del Prete, Rosita, Liguori, Ludovica, Cimmaruta, Chiara, Lukas, Jan, Cubellis, Maria Vittoria, Andreotti, Giuseppina
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27-10-2016; Public Library of Science (PLoS)
• Subjects: a-Galactosidase; Allosteric properties; Allosteric Site - drug effects; alpha-Galactosidase - chemistry; alpha-Galactosidase - genetics; alpha-Galactosidase - metabolism; Animals; Binding sites; Bioinformatics; Biology and Life Sciences; Catalytic Domain; Chaperones; Chlorocebus aethiops; Computer engineering; COS Cells; Disease; Docking; Drug dosages; Enzymes; Fabry Disease - drug therapy; Fabry Disease - enzymology; Fabry Disease - genetics; Fabry's disease; Galactose; Galactosidase; Genetic aspects; Genotypes; Humans; Ligands; Lysosomes - enzymology; Medical screening; Medicine and Health Sciences; Methods; Missense mutation; Molecular Docking Simulation; Mutation; Pharmacology; Physical Sciences; Proteins; Purines - metabolism; Purines - pharmacology; Purines - therapeutic use; Research and Analysis Methods; Italy; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0165463

Personalized therapies are required for Fabry disease due to its large phenotypic spectrum and numerous different genotypes. In principle, missense mutations that do not affect the active site could be rescued with pharmacological chaperones. At present pharmacological chaperones for Fabry disease bind the active site and couple a stabilizing effect, which is required, to an inhibitory effect, which is deleterious. By in silico docking we identified an allosteric hot-spot for ligand binding where a drug-like compound, 2,6-dithiopurine, binds preferentially. 2,6-dithiopurine stabilizes lysosomal alpha-galactosidase in vitro and rescues a mutant that is not responsive to a mono-therapy with previously described pharmacological chaperones, 1-deoxygalactonojirimycin and galactose in a cell based assay.