Dual target approach for the treatment of Gaucher disease: new antioxidant pH-sensitive pharmacological chaperones

Pharmacological chaperones (PCs) are small molecules that are able to pass the blood brain barrier and bind and stabilize enzymes, rescuing the enzymatic activity of misfolded or deficient enzymes, when they are used at sub-inhibitory concentration. In particular, it is of great interest the search for PCs able to improve the cellular folding and trafficking defects associated with Gaucher disease (GD), the most common autosomal recessive lysosomal storage disorder. GD is caused by point mutations in the gene encoding for acid-β-glucosidase (GCase), the enzyme responsible for glucosylceramide (GlcCer) metabolism into glucose and ceramide. The aim of this research is the development and preclinical evaluation of a novel collection of pH-sensitive N-alkylated trihydroxypiperidines decorated with antioxidant moiety as potential multitarget agents for the treatment of GD. These compounds are potential able to a) target enzyme disfunction modulating the affinity for GCase inside the lysosomes thanks to pH-sensitive fragment, in order to maximize the PC activity with respect to the inhibitory behaviour, b) reduce high oxidative stress observed in GD patients thanks to antioxidant motif and c) address the neuropathic forms of GD. As a further advantage, based on our previous data on analogous compounds, the molecules proposed in this project are expected to have limited toxicity on cell lines, which augurs well for their development as new drugs for GD.