Glucocerebrosidase (GCase) activity modulation by 2-alkyl trihydroxypiperidines: Inhibition and pharmacological chaperoning
| Autor: | S. Giachetti, Francesca Clemente, Francesca Cardona, C. Cresti, Paolo De Paoli, Amelia Morrone, Macarena Martínez-Bailén, Cristina Faggi, Andrea Goti, Camilla Matassini |
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| Rok vydání: | 2020 |
| Předmět: |
Cell Survival
medicine.disease_cause 01 natural sciences Biochemistry Nitrone Structure-Activity Relationship Piperidines Drug Discovery medicine Humans Structure–activity relationship Enzyme Inhibitors Molecular Biology IC50 chemistry.chemical_classification Mutation Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Organic Chemistry Fibroblasts Enzyme assay 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Enzyme chemistry biology.protein Glucosylceramidase Stereoselectivity Glucocerebrosidase |
| Zdroj: | Bioorganic Chemistry. 98:103740 |
| ISSN: | 0045-2068 |
| DOI: | 10.1016/j.bioorg.2020.103740 |
| Popis: | The enzyme glucocerebrosidase (GCase) has become an important therapeutic target due to its involvement in pathological disorders consequent to enzyme deficiency, such as the lysosomal storage Gaucher disease (GD) and the neurological Parkinson disease (PD). Pharmacological chaperones (PCs) are small compounds able to stabilize enzymes when used at sub-inhibitory concentrations, thus rescuing enzyme activity. We report the stereodivergent synthesis of trihydroxypiperidines alkylated at C-2 with both configurations, by means of the stereoselective addition of Grignard reagents to a carbohydrate-derived nitrone in the presence or absence of Lewis acids. All the target compounds behave as good GCase inhibitors, with IC50 in the micromolar range. Moreover, compound 11a behaves as a PC in fibroblasts derived from Gaucher patients bearing the N370/RecNcil mutation and the homozygous L444P mutation, rescuing the activity of the deficient enzyme by up to 1.9- and 1.8-fold, respectively. Rescues of 1.2-1.4-fold were also observed in wild-type fibroblasts, which is important for targeting sporadic forms of PD. |
| Databáze: | OpenAIRE |
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