Inhibition of Aβ42 Peptide Aggregation by a Binuclear Ruthenium(II)-Platinum(II) Complex: Potential for Multimetal Organometallics as Anti-amyloid Agents

Design of inhibitors for amyloid-beta (A beta) peptide aggregation has been widely investigated over the years toward developing viable therapeutic agents for Alzheimer's disease (AD). The biggest challenge seems to be inhibiting A beta aggregation at the early stages possibly at the monomeric level, because oligomers are known to be neurotoxic. In this regard, exploiting the metal-chelating property of A beta to generate molecules that can overcome this impediment presents some promise. Recently, one such metal complex containing Pt-II ([Pt(BPS)Cl-2]) was reported to effectively inhibit A beta 42 aggregation and toxicity (Barnham, et al. (2008) Proc. Nail. Acad. Sci. U.S.A. 105, 6813). This complex was able bind to A beta 42 at the N-terminal part of the peptide and triggered a conformatio:nal change resulting in effective inhibition. In the current report, we have generated a mixed-binuclear metal complex containing Pt-II and Run metal centers that inhibited A beta 42 aggregation at an early stage and seemed to have different modes of interaction than the previously reported Pt-II complex, suggesting an important role of the second metal center. This 'proof-of-concept' compound will help in developing more effective molecules against A beta aggregation by modifying the two metal centers as well as their bridging ligands, which will open doors to new rationale for A beta inhibition.