Application of modular isoxazoline-β2,2-amino acid-based peptidomimetics as chemical model systems for studying the tau misfolding

Tau is a microtubule-associated protein essential for regulating microtubule dynamics and axonal transport in neurons. In tauopathies, the transition of tau from a physiological to a pathological form remains unclear, though the hexapeptides PHF6 and PHF6∗ are key in triggering aggregation. These sequences are shielded by a β-hairpin structure in the native state but expose hydrophobic residues during misfolding, promoting self-assembly. This study employs a non-natural β²-amino acid to induce PHF6 and PHF6∗ into either extended or β-hairpin conformations. The extended form triggers tau aggregation without additives, acting as a seed-competent monomer model system. Conversely, the β-hairpin preserves tau in a soluble monomeric state. Additionally, a β-hairpin mimic inspired by Hsp90 showed potential as a chaperone mimic and inhibitor of tau aggregation, offering insights into corrective folding and aggregation modulation in neuronal environments.