The ubiquitin-proteasome system (UPS) represents a critical pathway in maintaining cellular proteostasis by regulating protein degradation. Dysregulation in this system is implicated in neurodegenerative diseases, where the accumulation of misfolded proteins exacerbates proteotoxic stress. This dissertation investigates small-molecule activators of the 20S proteasome, leveraging its unique capacity to degrade intrinsically disordered proteins (IDPs) independent of ubiquitination. Through systematically exploring the structural and biochemical dynamics of proteasomal activation, the work delineates the therapeutic potential of targeting the 20S proteasome for neurodegenerative conditions.Initial studies characterized the interplay between protein aggregation, oxidative stress, and proteostasis disruption in diseases like Parkinson's and Alzheimer’s. A focus was placed on α-synuclein (α-syn), an IDP whose aggregation is central to Parkinson's pathology. Chapter Two describes the design, synthesis, and biological evaluation of third-generation chlorpromazine analogs, highlighting their efficacy in promoting 20S proteasome-mediated degradation of α-syn aggregates. Structure-activity relationships (SARs) were established, demonstrating the importance of specific substitutions in enhancing selectivity and minimizing off-target effects. Subsequent investigations in Chapter Three assessed these compounds in cellular models of oxidative stress. The results revealed that 20S proteasome activators mitigate oxidative damage by selectively degrading carbonylated proteins while preserving mitochondrial function. Chapter Four extends this work by introducing a novel piperazinone-based scaffold for 20S proteasome activators. These studies underscore the therapeutic promise of modulating proteasomal activity, providing a framework for future drug development to restore proteostasis and combat neurodegenerative diseases. This dissertation advances our understanding of proteasomal regulation and offers a compelling strategy to address the molecular underpinnings of protein misfolding disorders. The findings pave the way for developing clinically viable interventions targeting proteostasis networks, with significant implications for treating age-related neurodegenerative diseases.
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