化学
对偶(语法数字)
药物发现
疾病
计算生物学
生物化学
医学
艺术
文学类
病理
生物
作者
Wentao Zhu,Wenqian Zhang,Jian Chen,Yichen Tong,Fang Xu,Jiyan Pang
标识
DOI:10.1021/acs.jmedchem.3c01719
摘要
The aggregation of specific proteins is a histopathological hallmark in various neurodegenerative diseases (NDs), among which Alpha-synuclein (α-Syn) and tau have received increased attention. The targeted protein degradation (TPD) strategy has been studied in the treatment of NDs, but multitarget bifunctional molecules have been ignored. Herein, a series of effective dual PROTAC degraders were developed, which could degrade α-Syn aggregates and total tau simultaneously. The degradation effects were evaluated in vitro, and the results showed that T3 could significantly knockdown α-Syn aggregates and total tau in the degradation efficiency with DC50 of 1.57 ± 0.55 and 4.09 ± 0.90 μM, respectively. Further mechanistic exploration showed that the degradation effect was mediated by the ubiquitin–proteasome system (UPS). Additionally, the therapeutic efficacy of T3 was confirmed in an MPTP-induced PD mouse model. Our results suggest that these dual PROTACs may provide a potential therapeutic strategy for NDs.
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