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A. Frydman-Marom; M. Convertino; R. Pellarin; A. Lampel; R. Shaltiel-Karyo; D. Segal; A. Caflisch; D.E. Shalev; E. Gazit

Journal: ACS Chem. Biol.
Year: 2011
Volume: 6
Issue: 11
Pages: 1265-1276
DOI: 10.1021/cb200103h
Type of Publication: Journal Article

Amyloid 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


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.