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Platinum(II) O,S Complexes Inhibit the Aggregation of Amyloid Model Systems.

ABSTRACT: Platinum(II) complexes with different cinnamic acid derivatives as ligands were investigated for their ability to inhibit the aggregation process of amyloid systems derived from A?, Yeast Prion Protein Sup35p and the C-terminal domain of nucleophosmin 1. Thioflavin T binding assays and circular dichroism data indicate that these compounds strongly inhibit the aggregation of investigated peptides exhibiting IC50 values in the micromolar range. MS analysis confirms the formation of adducts between peptides and Pt(II) complexes that are also able to reduce amyloid cytotoxicity in human SH-SY5Y neuroblastoma cells. Overall data suggests that bidentate ligands based on ?-hydroxy dithiocinnamic esters can be used to develop platinum or platinoid compounds with anti-amyloid aggregation properties.

SUBMITTER: Florio D

PROVIDER: S-EPMC6413125 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Platinum(II) O,S Complexes Inhibit the Aggregation of Amyloid Model Systems.

Florio Daniele D Malfitano Anna Maria AM Di Somma Sarah S Mügge Carolin C Weigand Wolfgang W Ferraro Giarita G Iacobucci Ilaria I Monti Maria M Morelli Giancarlo G Merlino Antonello A Marasco Daniela D

International journal of molecular sciences 20190214 4

Platinum(II) complexes with different cinnamic acid derivatives as ligands were investigated for their ability to inhibit the aggregation process of amyloid systems derived from Aβ, Yeast Prion Protein Sup35p and the C-terminal domain of nucleophosmin 1. Thioflavin T binding assays and circular dichroism data indicate that these compounds strongly inhibit the aggregation of investigated peptides exhibiting IC50 values in the micromolar range. MS analysis confirms the formation of addu ...[more]

PMID: 30769904

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Project description:The misfolding and aggregation of amyloid-β (Aβ) peptides into amyloid fibrils is regarded as one of the causative events in the pathogenesis of Alzheimer's disease (AD). Tanshinones extracted from Chinese herb Danshen (Salvia Miltiorrhiza Bunge) were traditionally used as anti-inflammation and cerebrovascular drugs due to their antioxidation and antiacetylcholinesterase effects. A number of studies have suggested that tanshinones could protect neuronal cells. In this work, we examine the inhibitory activity of tanshinone I (TS1) and tanshinone IIA (TS2), the two major components in the Danshen herb, on the aggregation and toxicity of Aβ1-42 using atomic force microscopy (AFM), thioflavin-T (ThT) fluorescence assay, cell viability assay, and molecular dynamics (MD) simulations. AFM and ThT results show that both TS1 and TS2 exhibit different inhibitory abilities to prevent unseeded amyloid fibril formation and to disaggregate preformed amyloid fibrils, in which TS1 shows better inhibitory potency than TS2. Live/dead assay further confirms that introduction of a very small amount of tanshinones enables protection of cultured SH-SY5Y cells against Aβ-induced cell toxicity. Comparative MD simulation results reveal a general tanshinone binding mode to prevent Aβ peptide association, showing that both TS1 and TS2 preferentially bind to a hydrophobic β-sheet groove formed by the C-terminal residues of I31-M35 and M35-V39 and several aromatic residues. Meanwhile, the differences in binding distribution, residues, sites, population, and affinity between TS1-Aβ and TS2-Aβ systems also interpret different inhibitory effects on Aβ aggregation as observed by in vitro experiments. More importantly, due to nonspecific binding mode of tanshinones, it is expected that tanshinones would have a general inhibitory efficacy of a wide range of amyloid peptides. These findings suggest that tanshinones, particularly TS1 compound, offer promising lead compounds with dual protective role in anti-inflammation and antiaggregation for further development of Aβ inhibitors to prevent and disaggregate amyloid formation.

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Platinum(II) O,S Complexes Inhibit the Aggregation of Amyloid Model Systems.

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Platinum(II) <i>O</i>,<i>S</i> Complexes Inhibit the Aggregation of Amyloid Model Systems.

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