Inhibiting the toxic aggregation of amyloid-β and the tau protein, the key pathological agents involved in Alzheimer's, is a leading approach in modulating disease progression. Using an aggregative tau-derived model peptide, Ac-PHF6-NH2, the substitution of its amino acids with proline, a known efficient β-breaker, is shown to reduce self-assembly. This effect is attributed to the steric hindrance created by the proline substitution, which results in disruption of the β-sheet formation process. Moreover, several of the proline-substituted peptides inhibit the aggregation of Ac-PHF6-NH2 amyloidogenic peptide. Two of these modified inhibitors also disassemble pre-formed Ac-PHF6-NH2 fibrils and one inhibits induced cytotoxicity of the fibrils. Taken together, these lead β-breaker peptides may be developed into novel Alzheimer's disease therapeutics.
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- neurodegenerative diseases
- phf6 peptide
- protein self-assembly