Protein misfolding diseases, such as Parkinson’s Disease (PD) and related neurodegenerative disorders, are among the fastest growing health concerns globally.1 At present, however, their increasing incidence has not been matched by the development of targeted therapeutics for these diseases. PD is characterised by the misfolding and aggregation of the 14kDa protein α-synuclein, an intrinsically disordered protein involved in membrane dynamics and neurotransmission.1 Oligomeric and fibrillar aggregates produced during this process are highly cytotoxic, resulting in neuronal death and progressive neurodegeneration.2 As such, inhibition or modulation of this aggregation pathway is of great interest in the development of targeted therapeutics against PD. In this project, we have undertaken a natural products bioprospecting approach using brewer’s spent grain (BSG), a major byproduct of the brewing industry, to uncover new compounds that modulate α-synuclein structure and aggregation dynamics. Phenolic extracts obtained from BSG using conventional (NaOH) and eco-friendly deep eutectic solvents (choline chloride/maleic acid) were investigated to ascertain their ability to inhibit or modulate α-synuclein aggregation. These extracts contain a range of polyphenols such as hydroxycinnamic acids and hordatines, providing a structurally diverse screening library. Extracts demonstrated potent inhibition of α-synuclein fibril elongation in fluorescence kinetic assays, against both WT and PD-associated mutants (A53T & E46K). Conformational alterations were also observed in fibrils formed in the presence of BSG extracts, with extract-treated fibrils displaying decreased surface hydrophobicity as measured via Nile Red fluorescence. Global alterations in fibril morphology upon extract treatment were also apparent when visualised via transmission electron microscopy. Strikingly, native ion-mobility mass spectrometry revealed extract-specific modulation of α-synuclein monomer conformations, which direct specific aggregation and fibrilisation pathways. Together, these findings demonstrate modulation of both fibrillar and pre-fibrillar α-synuclein species by BSG extracts, suggesting these extracts are a promising source of aggregation modulators for downstream therapeutic development for PD and other protein misfolding disorders.