title: The myo-1,2-Diaminocyclitol Scaffold Defines Potent Glucocerebrosidase Activators and Promising Pharmacological Chaperones for Gaucher Disease.
abstract: A series of cyclitol derivatives with myo-configuration are β-glucocerebrosidase (GCase) inhibitors and show excellent characteristics for the development of pharmacological chaperones for enzyme deficiency in Gaucher disease (GD). The most potent inhibitor, (1S,2R,3R,4S,5R,6S)-5,6-bis(nonylamino)cyclohexane-1,2,3,4-tetraol, displayed a K i value of 26 nM in isolated enzyme and also inhibited GCase in wild-type (wt) human fibroblasts at nanomolar concentrations. This diaminocyclitol produced maximum increases of GCase activities of 60% in N370S lymphoblasts at 100 nM and 30% in L444P at 1 nM following a 3-day incubation, showing the permeability, subcellular distribution, and cell metabolism characteristics for use as pharmacological chaperone.
authors.affiliation: Research Unit on Bioactive Molecules (RUBAM), Departament de Química Biomèdica, Institut de Química Avançada de Catalunya (IQAC-CSIC) , Jordi Girona 18-26, 08034 Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Trapero
authors.affiliation: Research Unit on Bioactive Molecules (RUBAM), Departament de Química Biomèdica, Institut de Química Avançada de Catalunya (IQAC-CSIC) , Jordi Girona 18-26, 08034 Barcelona, Spain.
authors.forename: Amadeu
authors.initials: A
authors.lastname: Llebaria
keywords: Gaucher disease; L444P mutation; N370S mutation; cyclitol; pharmacological chaperone; β-glucocerebrosidase