Small molecule inhibitors targeting alpha-synuclein aggregation: Progress and future outlook

Parkinson's disease (PD), a progressive neurodegenerative disorder, is primarily characterized by the accumulation of alpha-synuclein (α-syn) aggregates in the brain, leading to the neuronal dysfunction and degeneration. As a result, targeting α-syn aggregation is emerging as a promising therapeutic strategy for delaying or stopping disease progression. The present chapter tried to explore the progress made in the development of small molecule inhibitors in preventing or reversing the aggregation of α-syn. Overall, the chapter provides an overview of the mechanisms underlying α-syn misfolding and aggregation, and highlights potential small molecules inhibitors of α-syn aggregation with an update about their clinical trial studies. The chapter also provides current status of clinical trials of these inhibitors. Furthermore, emerging strategies including combination therapies, multi-target approaches, and small molecule-based chaperone therapeutics that might enhance the efficacy of these small molecule inhibitors are discussed. Future directions are also highlighted, emphasizing the emerging potential of small molecule inhibitors in disease-modifying treatments for PD.