Natural L-Hexapeptides with Therapeutic Potential for Alzheimer’s Disease and Tauopathies

Alzheimer's disease and tauopathies are partly caused by tau protein fibrillation. The tau's PHF6/β1 sequence ₃₀₆VQIVYK₃₁₁ plays a central role in protein self-assembly, acting as a nucleation center. We aimed to identify new therapeutic hexapeptides that inhibit tau fibrillation by targeting the ₃₀₆VQIVYK₃₁₁ nucleation site. We designed hexapeptide batches derived from PHF6, with varying sequences but preserving key amino acid positions involved in the tau nucleation process. These hexapeptides were characterized and classified using a newly optimized biochemical method that we developed. Soluble hexapeptides were preselected because of their therapeutic potential and were selected by using the <i>in vitro</i> PHF6/β1 fibrillation model. Hexapeptides strongly inhibiting fibrillation rates at substoichiometric levels were selected as leads. Unlike related peptides classified as amyloids, the leads were found to be completely innocuous to neuroblastoma cell lines, even at high concentrations. Hexapeptides selected as leads are promising candidates for therapeutic purposes and can be used to develop molecules for biochemical diagnosis and probes for positron emission tomography (PET) imaging in the context of tauopathies, particularly Alzheimer's disease.