Development of a Systematic Strategy toward Promotion of α-Synuclein Aggregation Using 2-Hydroxyisophthalamide-Based Systems

Abstract

Establishing a potent scheme against α-synuclein aggregation involved in Parkinson’s disease has been evaluated as a promising route to identify compounds that either inhibit or promote the aggregation process of α-synuclein. In the last two decades, this perspective has guided a dramatic increase in the efforts, focused on developing potent drugs either for retardation or promotion of the self-assembly process of α-synuclein. To address this issue, using a chemical kinetics platform, we developed a strategy that enabled a progressively detailed analysis of the molecular events leading to protein aggregation at the microscopic level in the presence of a recently synthesized 2-hydroxyisophthalamide class of small organic molecules based on their binding affinity. Furthermore, qualitatively, we have developed a strategy of disintegration of α-synuclein fibrils in the presence of these organic molecules. Finally, we have shown that these organic molecules effectively suppress the toxicity of α-synuclein oligomers in neuron cells.