Design, Synthesis and Biological Evaluation of α-Synuclein Proteolysis-Targeting Chimeras

alpha-Synuclein aggregation under pathological conditions is one of the causes of related neurodegenerative diseases. PROTACs (proteolysis targeting chimeras) are bifunctional small molecules that induce a post-translational erasure of proteins via the ubiquitination of target proteins by E3 ubiquitin ligase and subsequent proteasomal degradation. However, few research studies have been conducted for targeted protein degradation of ff-synuclein aggregates. In this article, we have designed and synthesized a series of small-molecule degraders 1-9 based on a known alpha-synuclein aggregation inhibitor sery384. In silico docking studies of sery384 with ff-synuclein aggregates were accomplished to ensure that the compounds bound to alpha-synuclein aggregates specifically. The protein level of ff-synuclein aggregates was determined to evaluate the degradation efficiency of PROTAC molecules on ff-synuclein aggregates in vitro. The results show that compound 5 had the most significant degradation effect, with DC50 of 5.049 mu M, and could induce the degradation of alpha-synuclein aggregates in a time- and dose-dependent manner in vitro. Furthermore, compound 5 could inhibit the elevation of the ROS level caused by overexpression and aggregation of ff-synuclein and protect H293T cells from ff-synuclein toxicity. Conclusively, our results provide a new class of small-molecule degraders and an experimental basis for the treatment of alpha-synuclein related neurodegenerative diseases.