Neurodegenerative diseases effect millions of patients world-wide, however, there are insufficient available therapeutics to halt or slow down the progression of these diseases. A key histopathological feature of numerous neurodegenerative diseases, such as Parkinson’s Disease, is the oligomerization and aggregation of intrinsically disordered proteins (IDPs). The aggregates create neuronal deposits, such as Lewy Bodies in Parkinson’s Disease. The proteolytic degradation of these pathogenic, aggregation prone IDPs is mediated by the 20S human proteasome. Enhancing the 20S proteasome-mediated proteolysis offers a useful therapeutic pathway to prevent the buildup of these aggregates, and therefore neurotoxicity. Here, we report the successful development of sub- micromolar 20S proteasome activator, based on the phenothiazine scaffold. This class of compounds prevented the accumulation of a pathologically relevant IDP, pathogenic A53T mutated a -synuclein, <i>in vitro</i> and in mammalian cell lines

Design, synthesis and biological evaluation of potent 20S proteasome activators for treatment of neurodegenerative diseases

ACS Spring 2022

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