Structural basis for inhibiting ß-amyloid oligomerization by a non-coded ß-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 ß-breaker motif, as seen in several optimized inhibitors of Aß aggregation. The activity of native endomorphins was studied, as well as the rationally designed analogue Aib-1, which includes a remarkably efficient ß-breaker, α-aminoisobutyric acid (Aib). In vitro and GFP fusion protein assays showed that Aib-1 interacted with Aß and markedly inhibited the formation of toxic oligomer and fibril growth. Moreover, Aib-1 prevented the toxicity of Aß 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 Aß 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.