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

Department of Pathology, University of Melbourne, Parkville, Victoria, 3010, Australia.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2008; 105(19):6813-8. DOI: 10.1073/pnas.0800712105
Source: PubMed


Amelyoid-beta peptide (Abeta) is a major causative agent responsible for Alzheimer's disease (AD). Abeta 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-PtCl(2) (L = 1,10-phenanthroline derivatives) complexes were examined and shown to bind to Abeta, inhibit neurotoxicity and rescue Abeta-induced synaptotoxicity in mouse hippocampal slices. Coordination of the complexes to Abeta 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 Abeta. This implies that the planar aromatic 1,10-phenanthroline ligands L confer some specificity for Abeta onto the platinum complexes. The potent effect of the L-PtCl(2) complexes identifies this class of compounds as therapeutic agents for AD.

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    • "The structures of some L–PtCl 2 complexes used as possible inhibitors of Ab aggregation. Histidine residues His-6, -13, -14, the aromatic residues Phe-4, -19, -20, and Tyr-10 of Ab (see Fig. 3) have been proposed to be targeted by L–PtCl 2 with the polyaromatic ligands L (reprinted with permission from Barnham et al., 2008. Copyright 2006 National Academy of Sciences, U.S.A). "
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    ABSTRACT: Amyloid-β peptide (Aβ) varies in size from 39 to 43 amino acids and arises from sequential β- and γ-secretase processing of the amyloid precursor protein. Whereas the non-pathological role for Aβ is yet to be established, there is no disputing that Aβ is now widely regarded as central to the development of Alzheimer's disease (AD). The so named "amyloid cascade hypothesis" states that disease progression is the result of an increased Aβ burden in affected areas of the brain. To elucidate the Aβ role in AD, many analytical approaches have been proposed as suitable tools to investigate not only the total Aβ load but also many other issues that are considered crucial for AD, such as: (i) the aggregation state in which Aβ is present; (ii) its interaction with other species or metals; (iii) its ability to induce oxidative stress; and (iv) its degradative pathways. This review provides an insight into the use of mass spectrometry (MS) in the field of Aβ investigation aimed to assess its role in AD. In particular, the different MS-based approaches applied in vitro and in vivo that can provide detailed information on the above-mentioned issues are reviewed. Moreover, the advantages offered by the MS methods over all the other techniques are highlighted, together with the recent developments and uses of combined analytical approaches to detect and characterize Aβ.
    Mass Spectrometry Reviews 05/2011; 30(3):347-65. DOI:10.1002/mas.20281 · 7.71 Impact Factor
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    • "Importantly for this strategy, these residues span the metal binding residues His-6, His-13 and His-14. A range of L-PtCl2 complexes were examined in a variety of in vitro assays and shown to bind to Ab, inhibit neurotoxicity and rescue Ab-induced synaptotoxicity in mouse hippocampal slices (Barnham et al., 2008). Coordination of the complexes to Ab altered the chemical properties of the peptide inhibiting amyloid formation and the generation of ROS. "
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    ABSTRACT: Alzheimer's disease (AD) is the most common age related neurodegenerative disease. Currently, there are no disease modifying drugs, existing therapies only offer short-term symptomatic relief. Two of the pathognomonic indicators of AD are the presence of extracellular protein aggregates consisting primarily of the Aβ peptide and oxidative stress. Both of these phenomena can potentially be explained by the interactions of Aβ with metal ions. In addition, metal ions play a pivotal role in synaptic function and their homeostasis is tightly regulated. A breakdown in this metal homeostasis and the generation of toxic Aβ oligomers are likely to be responsible for the synaptic dysfunction associated with AD. Therefore, approaches that are designed to prevent Aβ metal interactions, inhibiting the formation of toxic Aβ species as well as restoring metal homeostasis may have potential as disease modifying strategies for treating AD. This review summarizes the physiological and pathological interactions that metal ions play in synaptic function with particular emphasis placed on interactions with Aβ. A variety of therapeutic strategies designed to address these pathological processes are also described. The most advanced of these strategies is the so-called 'metal protein attenuating compound' approach, with the lead molecule PBT2 having successfully completed early phase clinical trials. The success of these various strategies suggests that manipulating metal ion interactions offers multiple opportunities to develop disease modifying therapies for AD.
    British Journal of Pharmacology 05/2011; 163(2):211-9. DOI:10.1111/j.1476-5381.2011.01221.x · 4.84 Impact Factor
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    • "In this regard, exploiting the metal-chelating property of Aβ to generate molecules that can overcome this impediment presents some promise. Recently, one such metal complex containing Pt II ([Pt(BPS)Cl 2 ]) was reported to effectively inhibit Aβ42 aggregation and toxicity (Barnham, et al. (2008) Proc. Natl. "
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    ABSTRACT: Design of inhibitors for amyloid-β (Aβ) peptide aggregation has been widely investigated over the years towards developing viable therapeutic agents for Alzheimer's disease (AD). The biggest challenge seems to be inhibiting Aβ aggregation at the early stages of aggregation possibly at the monomeric level, as oligomers are known to be neurotoxic. In this regard, exploiting the metal chelating property of Aβ to generate molecules that can overcome this impediment presents some promise. Recently, one such metal complex containing Pt(II) ([Pt(BPS)Cl(2)]) was reported to effectively inhibit Aβ42 aggregation and toxicity (1). This complex was able bind to Aβ42 at the N-terminal part of the peptide and triggered a conformational change resulting in effective inhibition. In the current report, we have generated a mixed-binuclear metal complex containing Pt(II) and Ru(II) that inhibited Aβ42 aggregation at an early stage of aggregation and seemed to have different modes of interaction than the previously reported Pt(II) complex, suggesting an important role of the second metal center. This 'proof-of-concept' compound will help in developing more effective molecules against Aβ aggregation by modifying the two metal centers as well as their ligands, which will open doors to new rationale for Aβ inhibition.
    ACS Chemical Neuroscience 08/2010; 2010(10):691-701. DOI:10.1021/cn100046m · 4.36 Impact Factor
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