Platinum-based inhibitors of amyloid-β as therapeutic agents for Alzheimer's disease

被引：194

作者：

Barnham, Kevin J. ^{[1
,2
,3
]}

Kenche, Vijaya B. ^{[1
,2
,3
]}

Ciccotosto, Giuseppe D. ^{[1
,2
,3
]}

Smith, David P. ^{[1
]}

Tew, Deborah J. ^{[1
,2
,3
]}

Liu, Xiang ^{[1
,2
]}

Perez, Keyla ^{[1
,2
,3
]}

Cranston, Greg A. ^{[1
,2
,3
]}

Johanssen, Timothy J. ^{[1
,2
,3
]}

Volitakis, Irene ^{[1
,2
]}

Bush, Ashley I. ^{[1
,2
]}

Masters, Colin L. ^{[1
,2
,4
]}

White, Anthony R. ^{[1
,2
,4
]}

Smith, Jeffrey P. ^{[1
,2
]}

Cherny, Robert A. ^{[1
,2
]}

Cappai, Roberto ^{[1
,2
,3
]}

机构：

[1] Univ Melbourne, Dept Pathol, Parkville, Vic 3010, Australia

[2] Univ Melbourne, Mental Hlth Res Inst, Parkville, Vic 3010, Australia

[3] Univ Melbourne, Bio Inst Mol Sci & Biotechnol 21, Parkville, Vic 3010, Australia

[4] Univ Melbourne, Ctr Neurosci, Parkville, Vic 3010, Australia

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2008年 / 105卷 / 19期

基金：

英国惠康基金;

关键词：

D O I：

10.1073/pnas.0800712105

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 [理学]; 0710 [生物学]; 09 [农学];

摘要：

Amelyoid-beta peptide (A beta) is a major causative agent responsible for Alzheimer's disease (AD). A beta contains a high affinity metal binding site that modulates peptide aggregation and toxicity. Therefore, identifying molecules targeting this site represents a valid therapeutic strategy. To test this hypothesis, a range of L-PtCl2 (L = 1,10-phenanthroline derivatives) complexes were examined and shown to bind to A beta, inhibit neurotoxicity and rescue A beta-induced synaptotoxicity in mouse hippocampal slices. Coordination of the complexes to A beta altered the chemical properties of the peptide inhibiting amyloid formation and the generation of reactive oxygen species. In comparison, the classic anticancer drug cisplatin did not affect any of the biochemical and cellular effects of A beta. This implies that the planar aromatic 1,10-phenanthroline ligands L confer some specificity for A beta onto the platinum complexes. The potent effect of the L-PtCl2 complexes identifies this class of compounds as therapeutic agents for AD.

引用

页码：6813 / 6818

页数：6

共 24 条

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Characterization of copper interactions with Alzheimer amyloid β peptides:: Identification of an attomolar-affinity copper binding site on amyloid β1-42 [J].