Piperidine-based photoswitchable derivatives have been developed as putative pharmacological chaperones for glucocerebrosidase (GCase), the defective enzyme in Gaucher disease (GD). The structure-activity study revealed that both the iminosugar and the light-sensitive azobenzene are essential features to exert inhibitory activity towards human GCase and a system with the correct inhibition trend (IC50 of the light-activated form lower than IC50 of the dark form) was identified. Kinetic analyses showed that all compounds are non-competitive inhibitors (mixed or pure) of GCase and the enzyme allosteric site involved in the interaction was identified by means of MD simulations. A moderate activity enhancement of mutant GCase assessed in GD patients' fibroblasts (ex vivo experiments) carrying the most common mutation was recorded. This promising observation paves the way for further studies to improve the benefit of the light-to- dark thermal conversion for chaperoning activity.

Light-Triggered Control of Glucocerebrosidase Inhibitors: Towards Photoswitchable Pharmacological Chaperones / Francesca Clemente, Maria Giulia Davighi, Camilla Matassini, Francesca Cardona, Andrea Goti, Amelia Morrone, Paolo Paoli, Tomás Tejero, Pedro Merino, Martina Cacciarini. - In: CHEMISTRY. - ISSN 1521-3765. - ELETTRONICO. - 29:(2023), pp. 1-12. [10.1002/chem.202203841]

Light-Triggered Control of Glucocerebrosidase Inhibitors: Towards Photoswitchable Pharmacological Chaperones

Francesca Clemente;Maria Giulia Davighi;Camilla Matassini
;
Francesca Cardona;Andrea Goti;Amelia Morrone;Paolo Paoli;Martina Cacciarini
2023

Abstract

Piperidine-based photoswitchable derivatives have been developed as putative pharmacological chaperones for glucocerebrosidase (GCase), the defective enzyme in Gaucher disease (GD). The structure-activity study revealed that both the iminosugar and the light-sensitive azobenzene are essential features to exert inhibitory activity towards human GCase and a system with the correct inhibition trend (IC50 of the light-activated form lower than IC50 of the dark form) was identified. Kinetic analyses showed that all compounds are non-competitive inhibitors (mixed or pure) of GCase and the enzyme allosteric site involved in the interaction was identified by means of MD simulations. A moderate activity enhancement of mutant GCase assessed in GD patients' fibroblasts (ex vivo experiments) carrying the most common mutation was recorded. This promising observation paves the way for further studies to improve the benefit of the light-to- dark thermal conversion for chaperoning activity.
2023
29
1
12
Francesca Clemente, Maria Giulia Davighi, Camilla Matassini, Francesca Cardona, Andrea Goti, Amelia Morrone, Paolo Paoli, Tomás Tejero, Pedro Merino, Martina Cacciarini
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1300407
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