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조재흥 (Jaeheung Cho) 저자 이메일 보기
조회 765  인쇄하기 주소복사 트위터 공유 페이스북 공유 
Mechanistic Insights into Tunable Metal-Mediated Hydrolysis of Amyloid-β Peptides

Jeffrey S. Derrick, Jiwan Lee, Shin Jung C. Lee, Yujeong Kim§∥, Eunju Nam, Hyeonwoo Tak, Juhye Kang, Misun Lee, Sun Hee Kim*§∥, Kiyoung Park*‡, Jaeheung Cho*⊥, and Mi Hee Lim*† 

Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
§ Western Seoul Center, Korea Basic Science Institute (KBSI), Seoul 03759, Republic of Korea
Department of Chemistry and Nano Science, Ewha Womans University, Seoul 03760, Republic of Korea
Department of Emerging Materials Science, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Republic of Korea

*Corresponding authors

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 (Aβ>40 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 Aβ>40 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.

2017년 선정
- 형식: Research article
- 게재일: 2017년 01월 (BRIC 등록일 2017-01-23)
- 연구진: 국내연구진태극기
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조재흥 님 전체논문보기 >
Jeffrey S. Derrick (UNIST)
김선희 (한국기초과학지원연구원)
남원우 (이화여자대학교)
노현주 (DGIST)
박기영 (Stanford University)
임미희 (한국과학기술원 (KAIST))
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