A catalytic antioxidant for limiting amyloid-beta peptide aggregation and reactive oxygen species generation
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| Authors: | Gomes, LMF; Mahammed, A; Prosser, KE; Smith, JR; Silverman, MA; Walsby, CJ; Gross, Z; Storr, T |
| Year: | 2019 |
| Journal: | Chem. Sci. 10 Article Link (DOI) PubMed |
| Title: | A catalytic antioxidant for limiting amyloid-beta peptide aggregation and reactive oxygen species generation |
| Abstract: | Alzheimer's disease (AD) is a multifaceted disease that is characterized by increased oxidative stress, metal-ion dysregulation, and the formation of intracellular neurofibrillary tangles and extracellular amyloid-beta (A beta) aggregates. In this work we report the large affinity binding of the iron(III) 2,17-bis-sulfonato-5,10,15-tris(pentafluorophenyl)corrole complex FeL1 to the A beta peptide (K-d similar to 10(-7)) and the ability of the bound FeL1 to act as a catalytic antioxidant in both the presence and absence of Cu(II) ions. Specific findings are that: (a) an A beta histidine residue binds axially to FeL1; (b) that the resulting adduct is an efficient catalase; (c) this interaction restricts the formation of high molecular weight peptide aggregates. UV-Vis and electron paramagnetic resonance (EPR) studies show that although the binding of FeL1 does not influence the A beta-Cu(II) interaction (K-d similar to 10(-10)), bound FeL1 still acts as an antioxidant thereby significantly limiting reactive oxygen species (ROS) generation from A beta-Cu. Overall, FeL1 is shown to bind to the A beta peptide, and modulate peptide aggregation. In addition, FeL1 forms a ternary species with A beta-Cu(II) and impedes ROS generation, thus showing the promise of discrete metal complexes to limit the toxicity pathways of the A beta peptide. |
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