title: Identification of an Allosteric Binding Site on Human Lysosomal Alpha-Galactosidase Opens the Way to New Pharmacological Chaperones for Fabry Disease.
abstract: 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.
authors: Dipartimento di Biologia, Università Federico II, Napoli, 80126, Italy.
authors: Valentina
authors: V
authors: Citro
authors: Bioinformatics and High Performance Computing Research Group (BIO-HPC), Computer Engineering Department, Universidad Católica San Antonio de Murcia (UCAM), Spain.
authors: Jorge
authors: J
authors: Peña-García
authors: Bioinformatics and High Performance Computing Research Group (BIO-HPC), Computer Engineering Department, Universidad Católica San Antonio de Murcia (UCAM), Spain.
authors: Helena
authors: H
authors: den-Haan
authors: Bioinformatics and High Performance Computing Research Group (BIO-HPC), Computer Engineering Department, Universidad Católica San Antonio de Murcia (UCAM), Spain.
authors: Horacio
authors: H
authors: Pérez-Sánchez
authors: Dipartimento di Biologia, Università Federico II, Napoli, 80126, Italy.
authors: Rosita
authors: R
authors: Del Prete
authors: Dipartimento di Biologia, Università Federico II, Napoli, 80126, Italy.|Istituto di Chimica Biomolecolare-CNR, Pozzuoli, 80078, Italy.
authors: Ludovica
authors: L
authors: Liguori
authors: Dipartimento di Biologia, Università Federico II, Napoli, 80126, Italy.|Istituto di Chimica Biomolecolare-CNR, Pozzuoli, 80078, Italy.
authors: Chiara
authors: C
authors: Cimmaruta
authors: Albrecht-Kossel-Institute for Neuroregeneration, Medical University Rostock, Rostock, Germany.
authors: Jan
authors: J
authors: Lukas
authors: Dipartimento di Biologia, Università Federico II, Napoli, 80126, Italy.
authors: Maria Vittoria
authors: http://orcid.org/0000-0001-6147-6553
authors: MV
authors: Cubellis
authors: Istituto di Chimica Biomolecolare-CNR, Pozzuoli, 80078, Italy.
authors: Giuseppina
authors: G
authors: Andreotti
mesh_terms: D000495:Allosteric Site / Q000187:drug effects; D000818:Animals; D019556:COS Cells; D020134:Catalytic Domain; D002522:Chlorocebus aethiops; D000795:Fabry Disease / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008247:Lysosomes / Q000201:enzymology*; D062105:Molecular Docking Simulation; D009154:Mutation; D011687:Purines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000519:alpha-Galactosidase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D011687:Purines; C070898:2,6-dithiopurine; D000519:alpha-Galactosidase