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
Abstract
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 (IC 50 of the light‐activated form lower than IC 50 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.