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Inhibition of the Aggregation and Toxicity of the Minimal Amyloidogenic Fragment of Tau by Its Pro‐Substituted Analogues
Author(s) -
ChemerovskiGlikman Marina,
FrenkelPinter Moran,
Mdah Ragad,
AbuMokh Amjaad,
Gazit Ehud,
Segal Daniel
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201701218
Subject(s) - peptide , chemistry , fibril , proline , steric effects , cytotoxicity , amyloid (mycology) , protein aggregation , toxicity , biophysics , amino acid , biochemistry , stereochemistry , in vitro , biology , inorganic chemistry , organic chemistry
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‐NH 2 , 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‐NH 2 amyloidogenic peptide. Two of these modified inhibitors also disassemble pre‐formed Ac‐PHF6‐NH 2 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.