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Mechanistic Insights into Tunable Metal-Mediated Hydrolysis of Amyloid-beta Peptides

Title
Mechanistic Insights into Tunable Metal-Mediated Hydrolysis of Amyloid-beta Peptides
Authors
Derrick, Jeffrey S.Lee, JiwanLee, Shin Jung C.Kim, YujeongNam, EunjuTak, HyeonwooKang, JuhyeLee, MisunKim, Sun HeePark, KiyoungCho, JaeheungLim, Mi Hee
Ewha Authors
김선희
Issue Date
2017
Journal Title
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
ISSN
0002-7863JCR Link
Citation
vol. 139, no. 6, pp. 2234 - 2244
Publisher
AMER CHEMICAL SOC
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
An amyloidogenic peptide, amyloid-beta (A beta), 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 A beta (A beta(40) and A beta(42)) 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 A beta 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 A beta(40) and A beta(42) in living cells, proteolytic activity with A beta peptides under biologically relevant conditions, and inertness toward cleavage of structured proteins. Overall,, our approaches and findings on reactivities of divalent metal complexes toward Afi, along with the mechanistic insights, demonstrate the feasibility of utilizing such metal complexes for amyloid control.
DOI
10.1021/jacs.6b09681
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자연과학대학 > 화학·나노과학전공 > Journal papers
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