期刊
ACS APPLIED MATERIALS & INTERFACES
卷 12, 期 28, 页码 31182-31194出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsami.0c07745
关键词
neurodegenerative diseases; aggregation-induced emission; aggregation; inhibitors; molecular dynamics simulations
资金
- National Key RD Program [2018YFA0901700]
- National Natural Science Foundation of China [21878234, 21576199]
- Natural Science Foundation of Tianjin [18JCZDJC33000]
Amyloid self-assembly is pathologically linked to many neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). While many inhibitors have been developed individually for specific amyloid proteins, there are a few effective platforms to screen on a large scale general amyloid inhibitors against different amyloid proteins. Herein, we developed a new class of amyloid inhibitor probes by site-specific conjugation of aggregation-induced emission (AIE) molecules with amyloid proteins (i.e., AIE@amyloid probes) to realize a high-throughput screening of small-molecule inhibitors. Optimization of site-specific AIE conjugation with two amyloid proteins, amyloid-beta protein (A beta) and alpha-synuclein (alpha SN), enabled us to retain their high amyloidogenic properties; i.e., AIE-amyloid probes alone exhibited strong fluorescence due to amyloid-like aggregation, but they showed no fluorescence in the presence of amyloid inhibitors to prevent amyloid aggregation. From integration of AIE@amyloid probes and computational virtual screening from a large drug database, it was found that tolcapone possessed a dual inhibition against the aggregation and cytotoxicity of both A beta and alpha SN. More importantly, tolcapone significantly improved the spatial cognition and recognition of A beta-treated mice. This work represents an innovative attempt to design an AIE-based anti-amyloid drug platform for identifying new small-molecule inhibitors against amyloidogenesis in both AD and PD or other amyloid diseases.
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