Peptidic Scaffolds To Reduce the Interaction of Cu(II) Ions with β-Amyloid Protein.

Abstract

Competitive Cu(II)-binding studies have been carried out between five decapeptides (both acyclic and cyclic), namely C-Asp, C-Asn, O-Asp, ODPro-Asp, and O-Asn, and the Aβ(1-16) and Aβ(1-40) fragments. Conformational constraints in such peptidic scaffolds affect their copper-binding affinity, which can be tuned. In the present study, the ability of these peptides to compete with Aβ has been assessed in vitro, with the objective to examine whether such soft chelating agents may be used to lessen the deleterious interaction of Cu(II) with Aβ. Fluorescence spectroscopy, electron paramagnetic resonance, and mass spectrometry data show that the more constrained peptide, i.e., cyclic C-Asp, which displays a Cu(II)-binding affinity comparable to that of Aβ, is the only potential metal-protein attenuating compound (MPAC) candidate. In vitro aggregation studies with Aβ(1-40) reveal that C-Asp can hamper the formation of copper-stabilized oligomeric Aβ species, through capturing the metal ion prior to its interaction with monomeric Aβ. The present study shows that (cyclic) peptides, preorganized for Cu(II) binding, may be applied for the development of potential copper-Aβ attenuating compounds.