Design, Synthesis, and Biological Evaluation of Potent 20S Proteasome Activators for the Potential Treatment of α‑Synucleinopathies

While neurodegenerative diseases
affect millions of patients worldwide,
there are insufficient available therapeutics to halt or slow down
the progression of these diseases. A key pathological feature of several
neurodegenerative diseases is the oligomerization and aggregation
of specific intrinsically disordered proteins (IDPs) creating neuronal
deposits, such as Lewy bodies in Parkinson’s disease. Clearance
of these pathogenic, aggregation-prone IDPs is mediated by the 20S
isoform of the human proteasome. Thus, enhancing the 20S proteasome-mediated
proteolysis could be a very useful therapeutic pathway to prevent
neurotoxicity. Here, we report the successful development of sub-microM
20S proteasome activators based on a phenothiazine scaffold. This
class of compounds prevented the accumulation of pathologically relevant
IDPs, such as the pathogenic A53T mutated α-synuclein, in vitro and in mammalian cell lines.

神经退行性疾病（neurodegenerative diseases）影响全球数百万患者，但目前可用于阻断或延缓这类疾病进展的治疗手段仍十分匮乏。多种神经退行性疾病的关键病理特征之一，是特定内在无序蛋白（intrinsically disordered proteins, IDPs）发生寡聚化与聚集，形成神经元沉积灶——例如帕金森病中的路易小体（Lewy bodies）。这类具有致病性、易聚集的内在无序蛋白的清除过程，由人类蛋白酶体的20S亚型介导。因此，增强20S蛋白酶体介导的蛋白水解作用，或可成为预防神经毒性的有效治疗途径。本研究成功开发了基于吩噻嗪（phenothiazine）骨架的亚微摩尔级（sub-microM）20S蛋白酶体激活剂。该类化合物在体外及哺乳动物细胞系中，均可阻止病理性相关内在无序蛋白的积累，例如致病型A53T突变α-突触核蛋白（α-synuclein）。