Mixed Ligand Cu2+ Complexes of a Model Therapeutic with Alzheimer鈥檚 Amyloid-尾 Peptide and Monoamine Neurotransmitters

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• 作者：Vijaya B. Kenche ; Izabela Zawisza ; Colin L. Masters ; Wojciech Bal ; Kevin J. Barnham ; Simon C. Drew
• 刊名：Inorganic Chemistry
• 出版年：2013
• 出版时间：April 15, 2013
• 年：2013
• 卷：52
• 期：8
• 页码：4303-4318
• 全文大小：843K
• 年卷期：v.52,no.8(April 15, 2013)
• ISSN：1520-510X

文摘

8-Hydroxyquinolines (8HQ) have found widespread application in chemistry and biology due to their ability to complex a range of transition metal ions. The family of 2-substituted 8HQs has been proposed for use in the treatment of Alzheimer鈥檚 disease (AD). Most notably, the therapeutic PBT2 (Prana Biotechnology Ltd.) has been shown to act as an efficient metal chaperone, disaggregate metal-enriched amyloid plaques comprised of the A尾 peptide, inhibit Cu/A尾 redox chemistry, and reverse the AD phenotype in transgenic animal models. Yet surprisingly little is known about the molecular interactions at play. In this study, we show that the homologous ligand 2-[(dimethylamino)methyl]-8-hydroxyquinoline (HL) forms a CuL complex with a conditional (apparent) dissociation constant of 0.33 nM at pH 6.9 and is capable of forming ternary Cu²⁺ complexes with neurotransmitters including histamine (HA), glutamic acid (Glu), and glycine (Gly), with glutathione disulfide (GSSG), and with histidine (His) side chains of proteins and peptides including the A尾 peptide. Our findings suggest a molecular basis for the strong metal chaperone activity of PBT2, its ability to attenuate Cu²⁺/A尾 interactions, and its potential to promote neuroprotective and neuroregenerative effects.