Application of modular isoxazoline-β ^2,2 -amino acid-based peptidomimetic foldamers as a chemical model system for studying the tau misfolding mechanism

Tauopathies are a group of neurodegenerative diseases characterized by the deposition of abnormal aggregates of tau protein into the brain. Tau is a microtubule-associated protein whose physiological role is related to the modulation of microtubule dynamics and the correct axonal transport in neurons. In tauopathies, the mechanism of conversion of the tau molecule from a physiological to a pathological form is still unclear. Nevertheless, two hexapeptide sequences, named PHF6 and PHF6*, located in the R3 and R2 repetition domains of tau, respectively, seem to be crucial in triggering the aggregation. In the native state, the hydrophobic residues of PHF6 and PHF6* are protected by a β-hairpin-like structure. Contrary to that, the misfolded protein exposes hydrophobic residues, which can form hydrophobic interactions and drive the self-assembly process. Chemical model systems, other than being more straightforward and easily accessible than full-length proteins, can provide valuable insight, which is difficult to tease out by studying the natural systems directly, and can especially be employed to examine the structures and modes of folding of amyloid proteins. Here, we exploit the use of chemical systems to modulate and study the mechanism of tau misfolding and aggregation. By employing a new non-natural β ^2,2 -amino acid, we have induced the two hot spot sequences of tau (PHF6 and PHF6*) either to have a totally extended conformation or a β-hairpin, according to the (S) or (R) stereochemistry of the scaffold, respectively. The aim of this work was to provide, through the interchange between β-hairpin-like and extended conformations, a possible explanation for the mechanism of tau misfolding. We demonstrated that an extended conformation, exposing the hydrophobic residues of both sequences and driving away PHF6* from PHF6, can trigger the aggregation of tau and behaves as a seed-competent monomer model system. Conversely, a β-hairpin imitates the favorable folding of tau, allowing the protein to maintain its soluble monomeric form. Furthermore, a β-hairpin mimic, based on the chaperone protein Hsp90, demonstrated the further application of this type of peptidomimetic foldamers as both aggregation inhibitors and chaperone mimics for the corrective folding of tau in a neuronal environment.