Inhibition of the Aggregation and Toxicity of the Minimal Amyloidogenic Fragment of Tau by Its Pro-Substituted Analogues

Marina Chemerovski-Glikman, Moran Frenkel-Pinter, Ragad Mdah, Amjaad Abu-Mokh, Ehud Gazit, Daniel Segal*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)9618-9624
Number of pages7
JournalChemistry - A European Journal
Volume23
Issue number40
DOIs
StatePublished - 18 Jul 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Keywords

  • amyloid
  • neurodegenerative diseases
  • phf6 peptide
  • protein self-assembly
  • β-breaker

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