The small molecule ZPD‐2 inhibits the aggregation and seeded polymerisation of C‐terminally truncated α‐Synuclein

Protein aggregation, particularly the formation of amyloid fibrils, is associated with numerous human disorders, including Parkinson's disease. This neurodegenerative condition is characterised by the accumulation of α‐Synuclein amyloid fibrils within intraneuronal deposits known as Lewy bodies or neurites. C‐terminally truncated forms of α‐Synuclein are frequently observed in these inclusions in the brains of patients, and their increased aggregation propensity suggests a role in the disease's pathogenesis. This study demonstrates that the small molecule ZPD‐2 acts as a potent inhibitor of both the spontaneous and seeded amyloid polimerisation of C‐terminally truncated α‐Synuclein by interfering with early aggregation intermediates. This dual activity positions this molecule as a promising candidate for therapeutic development in treating synucleinopathies. The aggregation of α‐Synuclein plays a key role in Parkinson's disease. Remarkably, the C‐terminal region of this protein contributes to inhibit amyloid formation and its truncation enhances this process. In this work, we demonstrated that the addition of small molecules, ZPD‐2 or SynuClean‐D, inhibits the aggregation of C‐terminally truncated α‐Synuclein. Overall, the data suggested different inhibitory mechanisms with ZPD‐2 outperforming SC‐D by acting at the initial stages of aggregation.