DOI: 10.1021/acsomega.6c08401 ISSN: 2470-1343
A pH-Dependent Curcumin–Iminosugar Hybrid Promotes GCase Enhancement and Reactive Oxygen Species Reduction
Alessio Morano, Camilla Matassini, Francesca Cardona, Damiano Tanini, Silvia Falliano, Amelia Morrone, Rebecca Sodano, Paolo Paoli, Andrea Goti, Francesca ClementeAbstract
Gaucher disease and Parkinson’s disease are characterized by β-glucocerebrosidase (GCase) dysfunction and increased oxidative stress. Here, we report two multifunctional hybrids that combine an iminosugar-based pharmacological chaperone scaffold with curcumin- or ferulic acid-derived antioxidant motifs. The curcumin-iminosugar hybrid 2 exhibits pH-dependent GCase modulation, enhanced GCase activity under lysosomal conditions, enhanced enzyme activity in L444P Gaucher and wild-type fibroblasts, and reduced intracellular reactive oxygen species (ROS) levels. By integrating GCase enhancement and redox modulation within a single molecular framework, compound 2 represents a promising lead for Gaucher disease and GCase-related synucleinopathies.