Identification of an Allosteric Binding Site on Human Lysosomal Alpha-Galactosidase Opens the Way to New Pharmacological Chaperones for Fabry Disease.
Valentina CitroJorge Peña-GarcíaHelena den-HaanHoracio Pérez-SánchezRosita Del PreteLudovica LiguoriChiara CimmarutaJan LukasMaria Vittoria CubellisGiuseppina AndreottiPublished in: PloS one (2016)
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.
Keyphrases
- heat shock
- replacement therapy
- small molecule
- endothelial cells
- molecular dynamics
- heart failure
- cell therapy
- emergency department
- high throughput
- oxidative stress
- mouse model
- autism spectrum disorder
- mesenchymal stem cells
- drug delivery
- cancer therapy
- atrial fibrillation
- bone marrow
- protein protein
- drug induced
- electronic health record