PtCl2(phen) disrupts the metal ions binding to amyloid-β peptide

Abstract

Platinum phenanthroline complexes have been found to inhibit Aβ aggregation and reduce Aβ caused neurotoxicity. Our previous results revealed the synergistic roles of phenanthroline ligand and Pt(II) coordination in the inhibition of Aβ aggregation. In this work, the reactions of PtCl₂(phen) with metal bound Aβ complexes were investigated. HPLC results show that the copper coordination decreases the reaction rate of PtCl₂(phen) with Aβ_1–16 and influences the distribution of products on HPLC profiles. EPR results reveal that Cu²⁺ remains coordinated to the Aβ peptide upon the binding of [Pt(phen)]²⁺, however, the Cu²⁺ coordination sites are changed. The formation of bimetallic coordination complex [Pt(phen)+Aβ_1–16+Cu^II] was confirmed by ESI-MS. Tandem MS analysis shows that, similar to the reaction of apo-Aβ peptide, the His6/His14 chelation is also the preferred binding mode for [Pt(phen)]²⁺ in the presence of copper ions. EPR spectra suggest that the binding of [Pt(phen)]²⁺ alters the copper coordination from mode I to mode II in Aβ. Tandem MS analysis indicates that His13 and N-terminal amine could be involved in the Cu²⁺ coordination in the bimetallic adduct. Similar results were observed in the reaction of Zn²⁺ bound Aβ peptide, although the different zinc binding residues were detected in the bimetallic complex. These results indicate that the binding of platinum complex disturbs the most favorable coordination sphere of Cu²⁺/Zn²⁺ and turns these metal ions to the secondary coordination site on Aβ. The release of Cu²⁺/Zn²⁺ occurs at low pH. This result suggests that the binding of [Pt(phen)]²⁺ scaffold could interfere with the binding of Zn²⁺ and Cu²⁺ to Aβ, thus reducing the metal-induced Aβ aggregation and toxicity.