LAUSR

Amyloid-β (Aβ) oligomers are well-known toxic molecular species associated with Alzheimer's disease. Recent discoveries of the ability of amyloid fibril surfaces to convert soluble proteins into toxic oligomers suggested that these surfaces could serve as therapeutic targets for intervention. We have shown previously that a short helical peptide could be a key structural motif that can specifically recognize the K16-E22 region of Aβ40 fibril surface with an affinity at the level of several micromolar. Here, we demonstrated that in-tether chiral center-induced helical stabilized peptides were also able to recognize the fibril surfaces, effectively inhibiting the surface-mediated oligomerization of Aβ40. Moreover, through extensive computational sampling, we observed two distinct ways in which the peptide inhibitors recognize the fibril surface. Apart from a binding mode that, in accord with the original design, involves hydrophobic sidechains at the binding interface, we observed with a much higher chance another binding mode in which the hydrophobic staple interacts directly with the fibril surface. The affinity of the peptides for the fibril surface could be adjusted by tuning the hydrophobicity of the staple. The best candidate investigated here exhibits an affinity at sub-micromolar level (~0.75 μM). Collectively, this work opens an avenue for the rational design of candidate drugs with stapled peptides for amyloid-related disease.