Effects of Peptides Derived from Terminal Modifications of the Aβ Central Hydrophobic Core on Aβ Fibrillization

Considerable research effort has focused on the discovery of mitigators that block the toxicity of the beta-amyloid peptide (A beta) by targeting a specific step involved in A beta fibrillogenesis and subsequent aggregation. Given that aggregation intermediates are hypothesized to be responsible for A beta toxicity, such compounds could likely prevent or mitigate aggregation, or alternatively cause further association of toxic oligomers into larger nontoxic aggregates. Herein we investigate the effect of modifications of the KLVFF hydrophobic core of A beta by replacing N- and C-terminal groups with various polar moieties. Several of these terminal modifications were found to disrupt the formation of amyloid fibrils and in some cases induced the disassembly of preformed fibrils. Significantly, mitigators that incorporate MiniPEG polar groups were found to be effective against A beta(1-40) fibrilligonesis. Previously, we have shown that mitigators incorporating alpha,alpha-disubstituted amino acids (alpha alpha AAs) were effective in disrupting fibril formation as well as inducing fibril disassembly. In this work, we further disclose that the number of polar residues (six) and alpha alpha AAs (three) in the original mitigator can be reduced without dramatically changing the ability to disrupt A beta(1-40) fibrillization in vitro.