Fibrilpaint: A Class of Amyloid-Targeting Peptides.

Amyloid fibrils are a common pathological hallmark in multiple neurodegenerative diseases, yet molecular tools to recognize and manipulate them remain scarce. We report FibrilPaints, a family of modular peptides designed for amyloid binding and adaptable chemical functionality. The degenerative amyloid-targeting unit of FibrilPaints, W5P4H3R2, 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 binding Tau and Huntingtin amyloid fibrils, with potential for broader detection and modulation applications.