Inhibition of A beta 42 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.