Dataset Information

Tryptophan-galactosylamine conjugates inhibit and disaggregate amyloid fibrils of A?42 and hIAPP peptides while reducing their toxicity.

ABSTRACT: Self-assembly of proteins into amyloid fibrils is a hallmark of various diseases, including Alzheimer's disease (AD) and Type-2 diabetes Mellitus (T2DM). Aggregation of specific peptides, like A?42 in AD and hIAPP in T2DM, causes cellular dysfunction resulting in the respective pathology. While these amyloidogenic proteins lack sequence homology, they all contain aromatic amino acids in their hydrophobic core that play a major role in their self-assembly. Targeting these aromatic residues by small molecules may be an attractive approach for inhibiting amyloid aggregation. Here, various biochemical and biophysical techniques revealed that a panel of tryptophan-galactosylamine conjugates significantly inhibit fibril formation of A?42 and hIAPP, and disassemble their pre-formed fibrils in a dose-dependent manner. They are also not toxic to mammalian cells and can reduce the cytotoxicity induced by A?42 and hIAPP aggregates. These tryptophan-galactosylamine conjugates can therefore serve as a scaffold for the development of therapeutics towards AD and T2DM.

SUBMITTER: Paul A

PROVIDER: S-EPMC7468108 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Tryptophan-galactosylamine conjugates inhibit and disaggregate amyloid fibrils of Aβ42 and hIAPP peptides while reducing their toxicity.

Paul Ashim A Frenkel-Pinter Moran M Escobar Alvarez Daniela D Milordini Giulia G Gazit Ehud E Zacco Elsa E Segal Daniel D

Communications biology 20200902 1

Self-assembly of proteins into amyloid fibrils is a hallmark of various diseases, including Alzheimer's disease (AD) and Type-2 diabetes Mellitus (T2DM). Aggregation of specific peptides, like Aβ42 in AD and hIAPP in T2DM, causes cellular dysfunction resulting in the respective pathology. While these amyloidogenic proteins lack sequence homology, they all contain aromatic amino acids in their hydrophobic core that play a major role in their self-assembly. Targeting these aromatic residues by sma ...[more]

PMID: 32879439

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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.

Dataset Information

Tryptophan-galactosylamine conjugates inhibit and disaggregate amyloid fibrils of A?42 and hIAPP peptides while reducing their toxicity.

Publications

Tryptophan-galactosylamine conjugates inhibit and disaggregate amyloid fibrils of Aβ42 and hIAPP peptides while reducing their toxicity.

Similar Datasets

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