title: Structural basis for inhibiting β-amyloid oligomerization by a non-coded β-breaker-substituted endomorphin analogue.
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.
authors: Department of Molecular Microbiology & Biotechnology, Tel-Aviv University, Israel.
authors: Anat
authors: A
authors: Frydman-Marom
authors: Marino
authors: M
authors: Convertino
authors: Riccardo
authors: R
authors: Pellarin
authors: Ayala
authors: A
authors: Lampel
authors: Ronit
authors: R
authors: Shaltiel-Karyo
authors: Daniel
authors: D
authors: Segal
authors: Amedeo
authors: A
authors: Caflisch
authors: Deborah E
authors: DE
authors: Shalev
authors: Ehud
authors: E
authors: Gazit
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004331:Drosophila melanogaster / Q000187:drug effects; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects*; D055550:Protein Stability; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D001688:Biological Products; D009842:Oligopeptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C105293:endomorphin 1; C105294:endomorphin 2