The study identifies angelic acid as a small-molecule lead that disrupts β-sheet-rich α-synuclein fibrils in vitro, docks to β-sheet interfaces across fibril polymorphs, fragments fibrils, and markedly reduces intracellular α-synuclein accumulation and modestly alleviates fibril-induced…

This paper presents an actionable, pathology-targeting lead with biophysical and cellular evidence for fibril disassembly, making it a promising starting point for medicinal chemistry optimization and in vivo evaluation toward a potential disease-modifying Parkinson's therapy.

Pathological aggregation of α-synuclein is a hallmark of synucleinopathies such as Parkinson's disease, where fibrillar α-synuclein aggregates drive neurodegeneration. Here, we aimed to identify small molecules capable of disassembling fibrillar α-synuclein aggregates by screening a natural product library using a plasmonic nanoparticle amyloid corona platform. Candidates were further ranked based on key physicochemical properties (molecular weight, solubility, and lipophilicity) associated with cell permeability and potential central nervous system accessibility. Through this analysis, angelic acid emerged as the top candidate. Physicochemical characterization, including circular dichroism, Fourier-transform infrared spectroscopy, transmission electron microscopy, and atomic force microscopy, demonstrated that angelic acid disrupts β-sheet-rich conformations and fragments α-synuclein fibrils. Molecular docking analysis suggested potential interactions of angelic acid with β-sheet interface regions across multiple α-synuclein fibril polymorphs. In a bimolecular fluorescence complementation cell model, angelic acid reduced intracellular α-synuclein accumulation by up to 91.4% at 100 μM. In addition, angelic acid alleviated α-synuclein fibril-induced cytotoxicity by 34.1%, demonstrating both reduced cellular α-synuclein levels and attenuation of α-synuclein fibril-induced cytotoxicity. Collectively, these findings suggest that angelic acid is a pathological α-synuclein-targeting lead compound for synucleinopathies, highlighting the need for further in vivo evaluation in synucleinopathy models.