Structure-based design of seed-competent proteomimetic macrocycles derived from 4R tauopathic folds

Tauopathies are a class of neurodegenerative disorders whose predominant feature is tau protein deposits in the brain. Misfolded tau has the capacity to seed the fibrillization of naïve tau, leading to the prion-like spread of aggregates. Tau protomers within filaments always exhibit cross-beta amyloid structure, but distinct conformations often correlate with specific diseases. An understanding of how these conformations impact seeding activity remains elusive. Identification of the minimal epitopes required for transcellular propagation represents a key step toward more relevant models of disease progression. Here, we implement a diversity-oriented peptide macrocyclization approach toward seed-competent miniature tau, or “mini-tau”, proteomimetics. Structural elucidation of a potent mini-tau macrocycle reveals several conformational features present in tau folds from patient-derived extracts. The potentiation of beta-arch form and function through peptide stapling has broad-ranging implications for the minimization and mimicry of other proteopathic amyloids.