PtCl2(phen) disrupts the metal ions binding to amyloid- peptide.
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Platinum phenanthroline complexes have been found to inhibit A aggregation and reduce A caused neurotoxicity. Our previous results revealed the synergistic roles of phenanthroline ligand and Pt(ii) coordination in the inhibition of A aggregation. In this work, the reactions of PtCl2(phen) with metal bound A complexes were investigated. HPLC results show that the copper coordination decreases the reaction rate of PtCl2(phen) with A1-16 and influences the distribution of products on HPLC profiles. EPR results reveal that Cu(2+) remains coordinated to the A peptide upon the binding of [Pt(phen)](2+), however, the Cu(2+) coordination sites are changed. The formation of bimetallic coordination complex [Pt(phen)+A1-16+Cu(II)] was confirmed by ESI-MS. Tandem MS analysis shows that, similar to the reaction of apo-A 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 A. Tandem MS analysis indicates that His13 and N-terminal amine could be involved in the Cu(2+) coordination in the bimetallic adduct. Similar results were observed in the reaction of Zn(2+) bound A 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 Cu(2+)/Zn(2+) and turns these metal ions to the secondary coordination site on A. The release of Cu(2+)/Zn(2+) occurs at low pH. This result suggests that the binding of [Pt(phen)](2+) scaffold could interfere with the binding of Zn(2+) and Cu(2+) to A, thus reducing the metal-induced A aggregation and toxicity.