Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-51368
Frydman-Marom, A; Convertino, M; Pellarin, R; Lampel, A; Shaltiel-Karyo, R; Segal, D; Caflisch, A; Shalev, D E; Gazit, E (2011). Structural basis for inhibiting β-amyloid oligomerization by a non-coded β-breaker-substituted endomorphin analogue. ACS Chemical Biology, 6(11):1265-1276.
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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.
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|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
|Dewey Decimal Classification:||570 Life sciences; biology|
|Deposited On:||29 Nov 2011 15:48|
|Last Modified:||20 Mar 2014 14:48|
|Publisher:||American Chemical Society|
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