FibrilPaint: a class of amyloid-targeting peptides

Amyloid fibrils are a common pathological hallmark in multiple neurodegenerative diseases, yet molecular tools to selectively recognise and manipulate them remain scarce. We report FibrilPaints, a family of modular peptides designed for selective amyloid binding and adaptable chemical functionality. The degenerative amyloid-targeting unit of FibrilPaints, W 5 P 4 H 3 R 2 , has a high content of π-stacking and aromatic side chains. Systematic sequence variation, altering charge, termini, and residue order, revealed the importance of the composition of the amyloid-targeting unit for high-affinity binding across Tau and Huntingtin fibrils. Importantly, sequence changes outside this unit do not preclude fibril binding, which permits attachment of fluorophores or E3-recruiting motifs for targeted protein degradation. This work establishes FibrilPaint as a modular peptide system for the detection and modulation of amyloids. Abstract Figure Figure of content The modular design of FibrilPaints enables systematic evaluation of their functionality by testing the binding capacity of each variant (FibrilPaintX) to distinct amyloid fibrils. Successful binding results in visible ‘painting’ of the fibrils, facilitating their detection and downstream research.