TY - JOUR

T1 - Light-Triggered Control of Glucocerebrosidase Inhibitors

T2 - Towards Photoswitchable Pharmacological Chaperones

AU - Clemente, Francesca

AU - Davighi, Maria Giulia

AU - Matassini, Camilla

AU - Cardona, Francesca

AU - Goti, Andrea

AU - Morrone, Amelia

AU - Paoli, Paolo

AU - Tejero, Tomás

AU - Merino, Pedro

AU - Cacciarini, Martina

N1 - Funding Information: MIUR ‐ progetto Dipartimenti di Eccellenza2018–2022 (ref. B96C1700020008), Centro Interdipartimentale Risonanza Magnetica (C.I.R.M.), Universitá di Firenze and Fondazione CRF (project: MuTaParGa) Regione Toscana (Bando Salute 2018, project: Lysolate are acknowledged for financial support. P.M. and T.T. thanks Ministerio de Ciencia e Innovacion (Spain) (Project PID2019‐104090RB‐100) and Government of Aragón (Spain) (Grupos Consolidados, E34_20R) for financial support. The authors thankfully acknowledge the resources from the supercomputers “Memento” and “Cierzo”, technical expertise and assistance provided by BIFI‐ZCAM (Universidad de Zaragoza, Spain). F.C. thanks DANEUROPARK for a postdoctoral fellowship. Open Access funding provided by Università degli Studi di Firenze within the CRUI‐CARE Agreement. i Publisher Copyright: © 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - gaucher disease

KW - glycomimetics

KW - molecular dynamics

KW - pharmacological chaperones

KW - photoswitches

U2 - 10.1002/chem.202203841

DO - 10.1002/chem.202203841

M3 - Journal article

C2 - 36598148

AN - SCOPUS:85149048389

VL - 29

JO - Chemistry: A European Journal

JF - Chemistry: A European Journal

SN - 0947-6539

IS - 19

M1 - e202203841

ER -