Fibrilpaint: A Class of Amyloid‐Targeting Peptides

ABSTRACT

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.