Evidence of α-Synuclein/Glucocerebrosidase Dual Targeting by Iminosugar Derivatives

Intrinsically disordered proteins (IDPs) are highly flexible molecules often linked to the onset of incurable diseases. Despite their great therapeutic potential, IDPs are often considered as undruggable because they lack defined binding pockets, which constitute the basis of drug discovery approaches. However, small molecules that interact with the intrinsically disordered state of α-synuclein, the protein linked to Parkinson's disease (PD), were recently identified and shown to act as chemical chaperones. Glucocerebrosidase (GCase) is an enzyme crucially involved in PD, since mutations that code for GCase are among the most frequent genetic risk factors for PD. Following the "dual-target" approach, stating that one carefully designed molecule can, in principle, interfere with more than one target, we identified a pharmacological chaperone for GCase that interacts with the intrinsically disordered monomeric form of α-synuclein. This result opens novel avenues to be explored in the search for molecules that act on dual targets, in particular, with challenging targets such as IDPs.