Peptide and Protein Mimetics Inhibiting Amyloid β-Peptide Aggregation

Abstract

Protein misfolding is related to some fatal diseases including Alzheimer’s disease (AD). Amyloid β-peptide (Aβ) generated from amyloid precursor protein can aggregate into amyloid fibrils, which are known to be a major component of Aβ deposits (senile plaques). The fibril formation of Aβ is typical of a nucleation-dependent process through self-recognition. Moreover, during fibrillization, several metastable intermediates such as soluble oligomers, including Aβ-derived diffusible ligands (ADDLs) and Aβ*56, are produced, which are thought to be the most toxic species to neuronal cells. Therefore, construction of molecules that decrease the Aβ aggregates, including soluble oligomers, protofibrils, and amyloid fibrils, might further our understanding of the mechanism(s) behind fibril formation and enable targeted drug discovery against AD. To this aim, various peptides and peptide derivatives have been constructed using the “Aβ binding element” based on the structural models of Aβ amyloid fibrils and the mechanisms of self-assembly. The central hydrophobic amino acid sequence, LVFF, of Aβ is a key sequence to self-assemble into amyloid fibrils. By combination of this core sequence with a hydrophobic or hydrophilic moiety, such as cholic acid or aminoethoxy ethoxy acetic acid units, respectively, good inhibitors of Aβ aggregation can be designed and synthesized. A peptide, LF, consisting of the sequence Ac-KQKLLLFLEE-NH₂, was designed based on the core sequence of Aβ but with a simplified amino acid sequence. The LF peptide can form amyloid-like fibrils that efficiently coassemble with mature Aβ1−42 fibrils. The LF peptide was also observed to immediately transform the soluble oligomers of Aβ1−42, which are thought to pose toxicity in AD, into amyloid-like fibrils. On the other hand, two Aβ-like β-strands with a parallel orientation were embedded in green fluorescent protein (GFP), comprised of a β-barrel structure, to make pseudo-Aβ β-sheets on its surface. The GFP variant P13H binds to Aβ1−42 and inhibits Aβ1−42 oligomerization effectively in a substoichiometric condition. Thus, molecules capable of binding to Aβ can be designed based on structural similarities with the Aβ molecule. The peptide and protein mimetics based on the structural features of Aβ might lead to the development of drug candidates against AD.