Mechanistic Insights into Tunable Metal-Mediated Hydrolysis of Amyloid‑β Peptides

An amyloidogenic
peptide, amyloid-β (Aβ), has been
implicated as a contributor to the neurotoxicity of Alzheimer’s
disease (AD) that continues to present a major socioeconomic burden
for our society. Recently, the use of metal complexes capable of cleaving
peptides has arisen as an efficient tactic for amyloid management;
unfortunately, little has been reported to pursue this strategy. Herein,
we report a novel approach to validate the hydrolytic cleavage of
divalent metal complexes toward two major isoforms of Aβ (Aβ40 and Aβ42) and tune their proteolytic activity
based on the choice of metal centers (M = Co, Ni, Cu, and Zn) which
could be correlated to their anti-amyloidogenic properties. Such metal-dependent
tunability was facilitated employing a tetra-N-methylated
cyclam (TMC) ligand that imparts unique geometric and stereochemical
control, which has not been available in previous systems. Co­(II)­(TMC)
was identified to noticeably cleave Aβ peptides and control
their aggregation, reporting the first Co­(II) complex for such reactivities
to the best of our knowledge. Through detailed mechanistic investigations
by biochemical, spectroscopic, mass spectrometric, and computational
studies, the critical importance of the coordination environment and
acidity of the aqua-bound complexes in promoting amide hydrolysis
was verified. The biological applicability of Co­(II)­(TMC) was also
illustrated via its potential blood-brain barrier permeability, relatively
low cytotoxicity, regulatory capability against toxicity induced by
both Aβ40 and Aβ42 in living cells,
proteolytic activity with Aβ peptides under biologically relevant
conditions, and inertness toward cleavage of structured proteins.
Overall, our approaches and findings on reactivities of divalent metal
complexes toward Aβ, along with the mechanistic insights, demonstrate
the feasibility of utilizing such metal complexes for amyloid control.