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

Abstract

Alzheimer's disease is characterized by the accumulation of amyloid-beta (A beta) aggregates, leading to neuronal degeneration and cognitive decline. Transition metal complexes have emerged as promising agents for chemically modifying A beta 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 A beta peptides remain scarce, however. Here we report the dual reactivity of a mononuclear Co(II) complex, [Co(TBDAP)(H2O)(NO3)](NO3) (1), toward A beta 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 A beta 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 O-2 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 A beta peptides mediated by 2 (inner-sphere hydride transfer between 2 and A beta, subsequent to decarboxylation and deamination of Asp1). Overall, our work provides valuable insights into the novel reactivities of transition metal complexes with A beta peptides, offering an innovative avenue to chemically transform A beta peptides through the utilization of these complexes.