FibrilPaint targets amyloid fibrils for ubiquitination

Abstract Neurodegenerative diseases are characterised by the progressive loss of neuronal tissue, and the accumulation of amyloid fibrils. Currently, there are no therapeutics that remove these amyloids. Targeted protein degradation could be a promising strategy to remove fibrils or oligomeric precursors. This approach requires degraders that specifically recognise amyloid fibrils, preferentially in early stages. Here, we introduce FibrilPaint20 (FP20), a peptide that specifically mediates the ubiquitination of amyloid fibrils. It acts as a PROTAC, containing both of a fibril recognition module and a recruitment motif for the E3 ubiquitin ligase CHIP. Importantly, FP20 does not bind to the functional monomer but exclusively to fibrils. Remarkably, FP20 ubiquitinates a set chemically diverse fibrils, unrelated in sequence and morphology. This includes fibrils of the disease-related proteins of α-synuclein, Aβ, Huntingtin and various Tau species, such as patient-derived fibrils from Alzheimer, Frontotemporal Dementia and Corticobasal Degeneration. This makes FP20 interesting for targeting mixed pathologies. Together, FP20 is an attractive lead compound for targeted protein degradation of amyloid fibrils.