Dual O₂-Mediated Reactivity of a Mononuclear Cobalt Complex with Amyloid-β Peptides

Alzheimer’s disease is characterized by the accumulation of amyloid-β (Aβ) aggregates, leading to neuronal degeneration and cognitive decline. Transition metal complexes have emerged as promising agents for chemically modifying Aβ peptides, owing to their versatile chemical reactivity, thereby altering their aggregation behavior and toxicity. Examples of transition metal complexes capable of inducing chemical transformations of Aβ peptides remain scarce, however. Here we report the dual reactivity of a mononuclear Co(II) complex, [Co(TBDAP)(H2O)(NO3)](NO3) (1), toward Aβ peptides in a site-specific manner. This reactivity includes chemical transformation at N-terminal Asp1, resulting in the generation of a pyruvamide moiety, and fragmentation between Val12 and His13. These site-specific chemical modifications achieved by 1 redirect the aggregation of Aβ peptides from on-pathway to off-pathway, yielding less toxic amorphous aggregates and relatively short fibrils. Our mechanistic investigations reveal that the oxidation of the Co(II) center to Co(III) by O2 is a crucial step for these reactivities, supported by similar reactivities observed with a newly synthesized Co(III) complex, [Co(TBDAP)(Cl)2](NO3) (2). Computational analyses further uncover the most energetically favorable, plausible reaction pathway for N-terminal chemical transformation of Aβ peptides mediated by 2 (inner-sphere hydride transfer between 2 and Aβ, subsequent to decarboxylation and deamination of Asp1). Overall, our work provides valuable insights into the novel reactivities of transition metal complexes with Aβ peptides, offering an innovative avenue to chemically transform Aβ peptides through the utilization of these complexes.