Metal complexation mechanisms of polyphenols associated to alzheimer’s disease

Polyphenols are a class of compounds, produced by plants, which share the ability to act as potent antioxidants. First investigations on polyphenols’ antioxidant activity are dated almost twenty years ago when their relationship and implication with the prevention and treatment of cancer was proposed for the first time. Later, in the early 2000s, the neuroprotective effects of several polyphenols were demonstrated. Nowadays, the benefits of a plethora of polyphenols have been studied and their ameliorating effects in several disease conditions, like cancer, cardiac and neuronal diseases are widely recognised. More than 1000 papers dealing with polyphenols and Alzheimer’s disease have been published so far, describing the antioxidant properties, the metal chelating features and the anti-aggregating behavior of these compounds. The aim of this review is to rationalize, from a chemical point of view, the metal complexation mechanisms of polyphenols related to two significant events of Alzheimer’s disease: oxidative stress and metal ion dyshomeostasis. In order to address this issue, we have herein discussed several aspects implicated in Alzheimer’s disease and polyphenols involved in the treatment of the disease

Metal compounds as inhibitors of B-amyloid aggregation. Perspectives for an innovative metallotherapeutics on Alzheimer’s disease

Alzheimer’s disease (AD) is a widespread neurodegenerative disease with a very high medical, social and economic burden. The etiopathogenesis of AD is still largely obscure; however, there is growing evidence that aggregation of -amyloid peptides (A) into a variety of supramolecular structures is critically involved in its insurgence and progression (the so called “amyloid cascade hypothesis”). Recent results point to oligomeric A aggregates rather than mature A fibrils as the major culprit for neurotoxicity; details of the inherent aggregation processes are being progressively clarified. In view of these achievements, early stages of A aggregation are considered today a realistic “druggable” target for the development of new anti-AD agents. Notably, a variety of organic compounds that are able to inhibit effectively A aggregation represent promising drug candidates. Metal based compounds capable of interacting with the N-terminal metal binding site of amyloid peptides might similarly contrast metalinduced A aggregation and serve as potential drugs for AD. In a recent pioneering study Barnham et al. showed that platinum(II) phenanthroline complexes strongly inhibit A oligomerisation and attenuate its neurotoxicity in vitro. A number of additional examples involving metal complexes as inhibitors of A aggregation were reported afterward. On the ground of those results it may be proposed that metal based compounds constitute today a suitable and rich source for novel anti-AD agents. The potential and the limits of this therapeutic option are comprehensively and critically discussed as well as the perspectives for future research

The role of His-50 of α-Synuclein in binding Cu(II): pH dependence, speciation, thermodynamics and structures

Copper interaction with alpha synuclein (αS) has been shown to accelerate aggregation and oligomerization of the protein. Three different αS copper binding domain have been proposed: (i) 10 the N-terminal residues (1-9) that represent the minimal copper binding domain; (ii) the His-50 imidazole and (iii) the Asp and Glu residues within the acidic C-terminal domain. The copper coordination at the N-terminus has been extensively characterized and it is generally accepted that it provides the highest affinity site. The same does not hold for the role played by His-50 in copper binding. In this work Cu(II) coordination to peptide fragments encompassing residues 45-55 of αS 15 has been exhaustively characterized, including systems containing the inherited mutations E46K and A53T, as model peptides of the His-50 site. Through potentiometic titrations all the speciation profiles have been determined and the stability constants have been used to estimate the dissociation constants of complexes corresponding to the binding modes at pH 6.5 and 7.5. Spectroscopic analyses allowed determination of (i) the copper coordination sphere, (ii) its 20 geometry and (iii) the constraints wherefrom the 3D structural models of the copper complexes could be obtained

Interaction of Angiotensin II with the C-terminal 300-320 fragment of the rat Angiotensin II Receptor AT1a monitored by NMR.

Interaction between angiotensin II (Ang II) and the fragment peptide 300–320 (fCT300–320) of the rat angiotensin II receptor AT1a was demonstrated by relaxation measurements, NOE effects, chemical shift variations, and CD measurements. The correlation times modulating dipolar interactions for the bound and free forms of Ang II were estimated by the ratio of the nonselective and single-selective longitudinal relaxation rates. The intermolecular NOEs observed in NOESY spectra between HN protons of 9LysfCT and 6Hisang, 10PhefCT and 8Pheang, HN proton of 3TyrfCT and Hα of 4Tyrang, 5PhefCTHδ and Hα of 4Tyrang indicated that Ang II aromatic residues are directly involved in the interaction, as also verified by relaxation data. Some fCT300–320 backbone features were inferred by the CSI method and CD experiments revealing that the presence of Ang II enhances the existential probability of helical conformations in the fCT fragment. Restrained molecular dynamics using the simulated annealing protocol was performed with intermolecular NOEs as constraints, imposing an α-helix backbone structure to fCT300–320 fragment. In the built model, one strongly preferred interaction was found that allows intermolecular stacking between aromatic rings and forces the peptide to wrap around the 6Leu side chain of the receptor fragment

How copper ions and membrane environment influence the structure of the human and chicken tandem repeats domain?

Prion proteins (PrPs) from different species have the enormous ability to anchor copper ions. The N-terminal domain of human prion protein (hPrP) contains four tandem repeats of the –PHGGGWGQ– octapeptide sequence. This octarepeat domain can bind up to four Cu 2+ ions. Similarly to hPrP, chicken prion protein (chPrP) is able to interact with Cu 2+ through the tandem hexapeptide -HNPGYP- region (residues 53–94). In this work, we focused on the human octapeptide repeat (human Octa 4 , hPrP 60–91 ) (Ac-PHGGGWGQPHGGGWGQPHGGGWGQPHGGGWGQ-NH 2 ) and chicken hexapeptide repeat (chicken Hexa 4 , chPrP 54–77 ) (Ac-HNPGYPHNPGYPHNPGYPHNPGYP-NH 2 ) prion protein fragments. Due to the fact that PrP is a membrane-anchored glycoprotein and its unstructured and flexible N-terminal domain may interact with the lipid bilayer, our studies were carried out in presence of the surfactant sodium dodecyl sulfate (SDS) mimicking the membrane environment in vitro. The main objective of this work was to understand the effects of copper ion on the structural rearrangements of the human and chicken N-terminal repeat domain. The obtained results provide a fundamental first step in describing the thermodynamic (potentiometric titrations) and structural properties of Cu(II) binding (UV–Vis, NMR, CD spectroscopy) to both human Octa 4 and chicken Hexa 4 repeats in both a DMSO/water and SDS micelle environment. Interestingly, in SDS environment, both ligands indicate different copper coordination modes, which results of the conformational changes in micelle environment. Our results strongly support that copper binding mode strongly depends on the protein backbone structure. Moreover, we focused on previously obtained results for amyloidogenic human and chicken fragments in membrane mimicking environment

THE UNUSUAL STABILIZATION OF THE Ni2+ AND Cu2+ COMPLEXES WITH NSFRY

The binding mode provided by an unprotected peptide with non-coordinating side-chains is simple and well understood. However, when particular residues are inserted into the peptide sequence, they can have a significant impact on the stability of the formed complexes. The presence of non-bonding side chains of amino acids close to the metal binding centre in the peptide/protein can provide special interactions which result in increasing the stabilization of the formed species. Moreover, these interactions can play a crucial role in generating particular protein structures and in influencing biological activity. In the present paper it is shown how peptides with no specific predisposition for metal binding, like ANF peptides, can form metal complexes with a very high thermodynamic stability. For better understanding this peculiar behavior, a combined pH-metric and spectroscopic method was used to determine the stability and the solution structure of Cu2+ and Ni2+ complexes with NSFRY-NH2 (ANF peptide) and a series of analogue peptides. All obtained data support the hypothesis that the complex-formation process is very similar for both metal ions and all the ligands, involving some intramolecular interactions among the different side chains. The two-dimensional NMR analysis of nickel complexes showed the occurrence of many inter-residue correlations and suggested the presence a direct interaction between the d electrons of the metal ion and the π-ring system of the aromatic side-chains of the ligand

Copper Binding to the Neurotoxic Peptide PrP106-126. Thermodynamic and Structural Studies

The human prion protein fragment PrP106-126 is a highly fibrillogenic peptide, resistant to proteinases and toxic to neurons; it derives from the normal prion protein (PrPC), with which it can interact, thus inhibiting its superoxide dismutase-like activity. The same properties are also shown by the abnormal isoform of the prion protein (PrPSc), and this similarity makes PrP106-126 an interesting model for the neurotoxic action of PrPSc. A role for copper in PrP106-126 aggregation and toxicity has recently been evidenced, and the interaction of terminal Lys, His and Met residues with the copper ion at neutral pH has been suggested. In order to shed more light on the the complex-formation equilibria of PrP106-126 with the copper ion, a thorough investigation has been carried out by means of several experimental techniques: potentiometry, solution calorimetry, VIS spectrophotometry, circular dichroism, EPR and NMR spectroscopy. A shorter and more soluble fragment-PrP106-113, which lacks the hydrophobic C-terminal domain of PrP106-126 but contains all the potential donor groups-has also been considered for the sake of comparison. The involvement of terminal amino, imidazolic and amido nitrogens in complex formation has been confirmed, while no evidence was found for the interaction of side chains of Met and Lys residues with the copper ion. Solution structures for the main complexes are suggested