Aggregation of amyloid peptides results in severe neurodegenerative diseases. While the fibril structures of Aβ40 and Aβ42 have been described recently, resolution of the aggregation pathway and evaluation of potent inhibitors still remains elusive, in particular in view of the hairpin-region of Aβ40. We here report the preparation of beta-turn mimetic conjugates containing synthetic turn mimetic structures in the turn region of Aβ40 and Aβ16-35, replacing 2 amino acids in the turn-region G25 – K28. The structure of the turn mimic induces both, acceleration of fibrillation and the complete inhibition of fibrillation, confirming the importance of the turn region on the aggregation. Replacing position G25-S26 provided the best inhibition effect for both beta-turn mimetics
Stefanie Deike, Sven Rothemund, Bruno Voigt, Suman Samantray, Birgit Strodel, Wolfgang Binder
Highlights:
Artificially modified amyloid Aβ40 – proteins are studied as a model system.
Synthetic beta-turn mimetic are conjugated into the turn region of Aβ40.
Both acceleration and retardation of fibrillation were observed.
Conformationally constrained turns reduce fibrillation, also in mixture with native Aβ40.
Conformationally flexible beta-turn-mimics lead to enhanced fibrillation.
Structural downsizing yields the modified Aβ16-35 as inhibitor of the aggregation of Aβ40.
https://doi.org/10.1016/j.bioorg.2020.104012
