Biomimetically Engineered Amyloid-Shelled Gold Nanocomplexes for Discovering α-Synuclein Oligomer-Degrading Drugs

The assembly of alpha-synuclein (alpha S) oligomers is recognized as the main pathological driver of synucleinopathies. While the elimination of toxic alpha S oligomers shows promise for the treatment of Parkinson's disease (PD), the discovery of alpha S oligomer degradation drugs has been hindered by the lack of proper drug screening tools. Here, we report a drug screening platform for monitoring the efficacy of alpha S-oligomer-degrading drugs using amyloid-shelled gold nanocomplexes (ASGNs). We fabricate ASGNs in the presence of dopamine, mimicking the in vivo generation process of pathological alpha S oligomers. To test our platform, the first of its kind for PD drugs, we use alpha S-degrading proteases and various small molecular substances that have shown efficacy in PD treatment. We demonstrate that the ASGN-based in vitro platform has strong potential to discover effective alpha S-oligomer-targeting drugs, and thus it may reduce the attrition problem in drug discovery for PD treatment.

Automated summary

We have developed a drug screening platform using amyloid-shelled gold nanocomplexes (ASGNs) to monitor the efficacy of alpha S-oligomer-degrading drugs. This platform mimics the in vivo generation process of pathological alpha S oligomers and has been tested using alpha S-degrading proteases and various small molecular substances with efficacy in PD treatment. Our results demonstrate that the ASGN-based in vitro platform has strong potential for discovering effective alpha S-oligomer-targeting drugs, thus reducing the attrition problem in drug discovery for PD treatment.