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Bifunctional compounds for controlling metal-mediated aggregation of the a?42 peptide.

ABSTRACT: Abnormal interactions of Cu and Zn ions with the amyloid ? (A?) peptide are proposed to play an important role in the pathogenesis of Alzheimer's disease (AD). Disruption of these metal-peptide interactions using chemical agents holds considerable promise as a therapeutic strategy to combat this incurable disease. Reported herein are two bifunctional compounds (BFCs) L1 and L2 that contain both amyloid-binding and metal-chelating molecular motifs. Both L1 and L2 exhibit high stability constants for Cu(2+) and Zn(2+) and thus are good chelators for these metal ions. In addition, L1 and L2 show strong affinity toward A? species. Both compounds are efficient inhibitors of the metal-mediated aggregation of the A?(42) peptide and promote disaggregation of amyloid fibrils, as observed by ThT fluorescence, native gel electrophoresis/Western blotting, and transmission electron microscopy (TEM). Interestingly, the formation of soluble A?(42) oligomers in the presence of metal ions and BFCs leads to an increased cellular toxicity. These results suggest that for the A?(42) peptide-in contrast to the A?(40) peptide-the previously employed strategy of inhibiting A? aggregation and promoting amyloid fibril dissagregation may not be optimal for the development of potential AD therapeutics, due to formation of neurotoxic soluble A?(42) oligomers.

SUBMITTER: Sharma AK

PROVIDER: S-EPMC3368506 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Bifunctional compounds for controlling metal-mediated aggregation of the aβ42 peptide.

Sharma Anuj K AK Pavlova Stephanie T ST Kim Jaekwang J Finkelstein Darren D Hawco Nicholas J NJ Rath Nigam P NP Kim Jungsu J Mirica Liviu M LM

Journal of the American Chemical Society 20120406 15

Abnormal interactions of Cu and Zn ions with the amyloid β (Aβ) peptide are proposed to play an important role in the pathogenesis of Alzheimer's disease (AD). Disruption of these metal-peptide interactions using chemical agents holds considerable promise as a therapeutic strategy to combat this incurable disease. Reported herein are two bifunctional compounds (BFCs) L1 and L2 that contain both amyloid-binding and metal-chelating molecular motifs. Both L1 and L2 exhibit high stability constants ...[more]

PMID: 22452395

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Project description:Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, with no cure and preventive therapy. Misfolding and extracellular aggregation of Amyloid-? (A?) peptides are recognized as the main cause of AD progression, leading to the formation of toxic A? oligomers and to the deposition of ?-amyloid plaques in the brain, representing the hallmarks of AD. Given the urgent need to provide alternative therapies, natural products serve as vital resources for novel drugs. In recent years, several natural compounds with different chemical structures, such as polyphenols, alkaloids, terpenes, flavonoids, tannins, saponins and vitamins from plants have received attention for their role against the neurodegenerative pathological processes. However, only for a small subset of them experimental evidences are provided on their mechanism of action. This review focuses on those natural compounds shown to interfere with A? aggregation by direct interaction with A? peptide and whose inhibitory mechanism has been investigated by means of biophysical and structural biology experimental approaches. In few cases, the combination of approaches offering a macroscopic characterization of the oligomers, such as TEM, AFM, fluorescence, together with high-resolution methods could shed light on the complex mechanism of inhibition. In particular, solution NMR spectroscopy, through peptide-based and ligand-based observation, was successfully employed to investigate the interactions of the natural compounds with both soluble NMR-visible (monomer and low molecular weight oligomers) and NMR-invisible (high molecular weight oligomers and protofibrils) species. The molecular determinants of the interaction of promising natural compounds are here compared to infer the chemical requirements of the inhibitors and the common mechanisms of inhibition. Most of the data converge to indicate that the A? regions relevant to perturb the aggregation cascade and regulate the toxicity of the stabilized oligomers, are the N-term and ?1 region. The ability of the natural aggregation inhibitors to cross the brain blood barrier, together with the tactics to improve their low bioavailability are discussed. The analysis of the data ensemble can provide a rationale for the selection of natural compounds as molecular scaffolds for the design of new therapeutic strategies against the progression of early and late stages of AD.

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Bifunctional compounds for controlling metal-mediated aggregation of the a?42 peptide.

Publications

Bifunctional compounds for controlling metal-mediated aggregation of the aβ42 peptide.

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