Structural basis for inhibiting β-amyloid oligomerization by a non-coded β-breaker-substituted endomorphin analogue

TitleStructural basis for inhibiting β-amyloid oligomerization by a non-coded β-breaker-substituted endomorphin analogue
Publication TypeJournal Article
Year of Publication2011
AuthorsFrydman-Marom A., Convertino M., Pellarin R., Lampel A., Shaltiel-Karyo R., Segal D., Caflisch A., Shalev D.E, Gazit E.
JournalACS Chemical Biology
Volume6
Issue11
Pagination1265-1276
Date Published2011 Nov 18
Type of ArticleResearch Article
ISSN1554-8937
KeywordsAmyloid beta-Peptides, Animals, Biological Products, Cell Survival, Cells, Cultured, Dose-Response Relationship, Drug, Drosophila melanogaster, Female, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Structure, Oligopeptides, PC12 Cells, Peptide Fragments, Protein Multimerization, Protein Stability, Rats, Structure-Activity Relationship
Abstract

The distribution of endomorphins (EM) 1 and 2 in the human brain inversely correlates with cerebral neurodegeneration in Alzheimer's disease (AD), implying a protective role. These endogenous opioid peptides incorporate aromatic residues and a β-breaker motif, as seen in several optimized inhibitors of Aβ aggregation. The activity of native endomorphins was studied, as well as the rationally designed analogue Aib-1, which includes a remarkably efficient β-breaker, α-aminoisobutyric acid (Aib). In vitro and GFP fusion protein assays showed that Aib-1 interacted with Aβ and markedly inhibited the formation of toxic oligomer and fibril growth. Moreover, Aib-1 prevented the toxicity of Aβ toward neuronal PC12 cells and markedly rectified reduced longevity of an AD fly model. Atomistic simulations and NMR-derived solution structures revealed that Aib-1 significantly reduced the propensity of Aβ to aggregate due to multimode interactions including aromatic, hydrophobic, and polar contacts. We suggest that hindering the self-assembly process by interfering with the aromatic core of amyloidogenic peptides may pave the way toward developing therapeutic agents to treat amyloid-associated diseases.

DOI10.1021/cb200103h
pubindex

0150

Alternate JournalACS Chem. Biol.
PubMed ID21892833
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