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

Abstract

Considerable research effort has focused on the discovery of mitigators that block the toxicity of the β-amyloid peptide (Aβ) by targeting a specific step involved in Aβ fibrillogenesis and subsequent aggregation. Given that aggregation intermediates are hypothesized to be responsible for Aβ 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 Aβ 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 Aβ 1-40 fibrilligonesis. Previously, we have shown that mitigators incorporating alpha,alpha-disubstituted amino acids (RRAAs) 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 RRAAs (three) in the original mitigator can be reduced without dramatically changing the ability to disrupt Aβ 1-40 fibrillization in vitro.

Thermodynamic and Structural Impact of α,α-Dialkylated Residue Incorporation in a β-Hairpin Peptide

“…11–15 Seeking to leverage this precedent toward biomedical application, recent studies have shown that strategic incorporation of bulky α,α-dialkylated amino acids (e.g., diisobutylglycine, dibenzylglycine, di- n -propylglycine) into short β-strands can cap growing β-sheets, preventing formation of amyloid fibrils and even promoting their disassembly. 16–18 …”

Electrochemical “Signal‐On” Reporter for Amyloid Aggregates

“…Spherical particles were previously reported for mixtures of Ab 1-40 with a Lys-Leu-Val-PhePhe-peptide-based inhibitor that has neutral mini-polyethylene glycol (PEG) groups at its C-and N-termini. [15] The incubation of Ab [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] with conjugates 3 and 4 resulted in the formation of mostly spherical particles (Figures 2 f and g). In the case of Ab 12-28 /4 no fibrils were observed.…”

“…These observations are supported by other results, indicating that hydrophobic and ionic interactions play an important role in the aggregation of Ab. [15] These effects may be responsible for the dramatic differences in the propensities of 1-4 to interfere with Ab aggregation.…”

“…[13] Several modifications of Lys-Leu-Val-Phe-Phe and Lys-Leu-Val-Phe-PheAla-Glu have been reported. [14][15][16] For example, N-methylation of the amide protons in Lys-Leu-Val-Phe-Phe and Lys-Leu-ValPhe-Phe-Ala-Glu resulted in the formation of peptides which are able to bind to Ab and disrupt its fibril formation.…”

Engineering of a peptide probe for β-amyloid aggregates

“…Importantly, small peptide ligands may serve as an alternative tool for the recognition of Ab aggregates and require no precise protein folding for binding to targets. 30,[37][38][39][40][41] However, potential of resulting peptides as a probe for Ab aggregates and the related binding sites within Ab have not been thoroughly examined. Peptide ligands can also be conjugated to other molecular scaffolds with precise control of spatial orientation, broadening the scope of sensing formats.…”