Identification of [PtCl2(phen)] binding modes in amyloid-ß peptide and the mechanism of aggregation inhibition.

Platinum phenanthroline complexes inhibit amyloid-ß (Aß) aggregation and reduce Aß-caused neurotoxicity [Proc. Natl. Acad. Sci., 2008, 105, 6813-6818]. In this study, we investigated the interactions of Aß(1-16) with [PtCl(2)(phen)] (phen=1,10-phenanthroline) using HPLC, ESI-MS, and NMR spectroscopy , and characterized the identity of products using tandem mass spectrometry. Results indicated that the phenanthroline ligand could induce noncovalent interactions between Aß peptide and platinum complexes, leading to rapid Aß platination. Multiple products were generated in the reaction, in which His6/His14 chelation was preferentially formed. Coordination of Asp7, His13, and Lys16 was also detected in other products. The majority of products were monoplatinated adducts with binding of the {Pt(phen)} scaffold, which impeded intermolecular interactions between Aß peptides. Moreover, noncovalent interactions were confirmed by the interaction between Aß peptide and [Pt(phen)(2)]Cl(2). The synergistic roles of the phen ligand and platinum(II) atom in the inhibition of Aß aggregation are discussed.