Covalent Modulation of Protein Misfolding and Aggregation Processes in the Context of Neurodegenerative Diseases

: Misfolded protein aggregates represent major histopathological hallmarks of neurodegenerative diseases, differing in the structural components and brain regions affected. Furthermore, the formed assemblies act as key players in developing and fostering neurotoxic processes, with distinct mechanisms depending on the stage of the amyloid cascade. Particularly, the oligomer intermediates are now considered as the main drivers of neurotoxicity, thus requiring an early antiaggregant therapeutic intervention to achieve a significant neuroprotective efficacy. Among different strategies, direct interaction at early stages preventing aggregation is quite intricate due to the considered undruggability of misfolded monomers. In this context, a covalent approach targeting specific functional nucleophilic residues within disordered proteins can offer an intriguing opportunity to overcome these weaknesses. Therefore, in this review, we outline covalent modulators of misfolding and aggregation processes reported to date, referring to the major misfolded proteins in the neurodegenerative context (i.e., β-amyloid, tau, α-synuclein, and superoxide dismutase 1) to highlight their potential both as valuable pharmacological tools or therapeutic perspectives.