| Autor: |
Tessa, Castellan, Virginie, Garcia, Frédéric, Rodriguez, Isabelle, Fabing, Yevhenii, Shchukin, My Lan, Tran, Stéphanie, Ballereau, Thierry, Levade, Yves, Génisson, Cécile, Dehoux |
| Rok vydání: |
2020 |
| Předmět: |
|
| Zdroj: |
Organicbiomolecular chemistry. 18(39) |
| ISSN: |
1477-0539 |
| Popis: |
A concise and asymmetric synthesis of the enantiomeric pyrrolidines 2 and ent-2 are herein reported. Both enantiomers were assessed as β-GCase inhibitors. While compound ent-2 acted as a poor competitive inhibitor, its enantiomer 2 proved to be a potent non-competitive inhibitor. Docking studies were carried out to substantiate their respective protein binding mode. Both pyrrolidines were also able to enhance lysosomal β-GCase residual activity in N370S homozygous Gaucher fibroblasts. Notably, the non-competitive inhibitor 2 displayed an enzyme activity enhancement comparable to that of reference compounds IFG and NN-DNJ. This work highlights the impact of inhibitors chirality on their protein binding mode and shows that, beyond competitive inhibitors, the study of non-competitive ones can lead to the identification of new relevant parmacological chaperones. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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