Light-triggered control of Glucocerebrosidase inhibitors: towards photoswitchable pharmacological Chaperones

Clemente, Francesca ; Davighi, Maria Giulia ; Matassini, Camilla ; Cardona, Francesca ; Goti, Andrea ; Morrone, Amelia ; Paoli, Paolo ; Tejero, Tomás (Universidad de Zaragoza) ; Merino, Pedro (Universidad de Zaragoza) ; Cacciarini, Martina

Resumen: 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.

Idioma: Inglés

DOI: 10.1002/chem.202203841

Año: 2023

Publicado en: Chemistry - A European Journal 29, 19 (2023), e202203841 [12 pp.]
ISSN: 0947-6539

Factor impacto JCR: 3.9 (2023)

Categ. JCR: CHEMISTRY, MULTIDISCIPLINARY rank: 80 / 231 = 0.346 (2023) - Q2 - T2

Factor impacto CITESCORE: 7.9 - Organic Chemistry (Q1) - Catalysis (Q2)

Factor impacto SCIMAGO: 1.058 - Chemistry (miscellaneous) (Q1) - Organic Chemistry (Q1) - Catalysis (Q2)

Financiación: info:eu-repo/grantAgreement/ES/DGA/E34-20R
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2019-104090RB-100

Tipo y forma: Article (Published version)

Área (Departamento): Área Química Orgánica (Dpto. Química Orgánica)