Native-MS as a suitable tool to select new scaffold for the inhibition of protein aggregation

Protein aggregation is a hallmark of numerous diseases, including neurodegenerative disorders, and presents significant challenges for drug discovery. A major obstacle in studying protein aggregation is the structural flexibility and heterogeneity of proteins, particularly intrinsically disordered proteins (IDPs), which lack a stable 3D structure. Traditional biophysical techniques often fail to capture the conformational diversity of these systems, hindering progress in understanding their aggregation pathways. Native mass spectrometry (MS) has emerged as a powerful approach to study the structure and dynamics of proteins in solution. Unlike denaturing methods, native MS preserves non-covalent interactions, enabling the analysis of protein conformations by examining charge-state distributions. This allows for the simultaneous characterization of compact, extended, and intermediate forms of proteins in a single experiment. The amyloid aggregation of α-synuclein (Syn), a key factor in Parkinson disease (PD), is influenced by genetic mutations such as E46K, which enhance aggregation propensity. Catechols have been shown to reduce amyloid fibril formation in a dose-dependent manner. Native MS reveal that this effect is conformation dependent, as the most aggregation-prone conformers of Syn and E46K are selected by these molecules and confined into off-pathway oligomers, preventing fibril formation. These findings highlight catechols as promising scaffolds for the design of therapeutics targeting protein aggregation in PD.