Dataset Information

Multivalent Polymer-Peptide Conjugates-A General Platform for Inhibiting Amyloid Beta Peptide Aggregation.

ABSTRACT: Protein aggregation is implicated in multiple deposition diseases including Alzheimer's Disease, which features the formation of toxic aggregates of amyloid beta (A?) peptides. Many inhibitors have been developed to impede or reverse A? aggregation. Multivalent inhibitors, however, have been largely overlooked despite the promise of high inhibition efficiency endowed by the multivalent nature of A? aggregates. In this work, we report the success of multivalent polymer-peptide conjugates (mPPCs) as a general class of inhibitors of the aggregation of A?40. Significantly delayed onset of fibril formation was realized using mPPCs prepared from three peptide/peptoid ligands covering a range of polymer molecular weights (MWs) and ligand loadings. Dose dependence studies showed that the nature of the ligands is a key factor in mPPC inhibition potency. The negatively charged ligand LPFFD (LD) leads to more efficient mPPCs compared to the neutral ligands, and is most effective at 7% ligand loading across different MWs. Molecular dynamics simulations along with dynamic light scattering experiments suggest that mPPCs form globular structures in solution due to ligand-ligand interactions. Such interactions are key to the spatial proximity of ligands and thus to the multivalency effect of mPPC inhibition. Excess ligand-ligand interactions, however, reduce the accessibility of mPPC ligands to A? peptides, and impair the overall inhibition potency.

SUBMITTER: Jiang X

PROVIDER: S-EPMC7059649 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Multivalent Polymer-Peptide Conjugates-A General Platform for Inhibiting Amyloid Beta Peptide Aggregation.

Jiang Xing X Halmes Abigail J AJ Licari Giuseppe G Smith John W JW Song Yang Y Moore Edwin G EG Chen Qian Q Tajkhorshid Emad E Rienstra Chad M CM Moore Jeffrey S JS

ACS macro letters 20190930 10

Protein aggregation is implicated in multiple deposition diseases including Alzheimer's Disease, which features the formation of toxic aggregates of amyloid beta (Aβ) peptides. Many inhibitors have been developed to impede or reverse Aβ aggregation. Multivalent inhibitors, however, have been largely overlooked despite the promise of high inhibition efficiency endowed by the multivalent nature of Aβ aggregates. In this work, we report the success of multivalent polymer-peptide conjugates (mPPCs) ...[more]

PMID: 32149017

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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.

Project description:Amyloid diseases are degenerative pathologies, highly prevalent today because they are closely related to aging, that have in common the erroneous folding of intrinsically disordered proteins (IDPs) which aggregate and lead to cell death. Type 2 Diabetes involves a peptide called human islet amyloid polypeptide (hIAPP), which undergoes a conformational change, triggering the aggregation process leading to amyloid aggregates and fibers rich in β-sheets mainly found in the pancreas of all diabetic patients. Inhibiting the aggregation of amyloid proteins has emerged as a relevant therapeutic approach and we have recently developed the design of acyclic flexible hairpins based on peptidic recognition sequences of the amyloid β peptide (Aβ1-42) as a successful strategy to inhibit its aggregation involved in Alzheimer's disease. The present work reports the extension of our strategy to hIAPP aggregation inhibitors. The design, synthesis, conformational analyses, and biophysical evaluations of dynamic β-hairpin like structures built on a piperidine-pyrrolidine β-turn inducer are described. By linking to this β-turn inducer three different arms (i) pentapeptide, (ii) tripeptide, and (iii) α/aza/aza/pseudotripeptide, we demonstrate that the careful selection of the peptide-based arms from the sequence of hIAPP allowed to selectively modulate its aggregation, while the peptide character can be decreased. Biophysical assays combining, Thioflavin-T fluorescence, transmission electronic microscopy, capillary electrophoresis, and mass spectrometry showed that the designed compounds inhibit both the oligomerization and the fibrillization of hIAPP. They are also capable to decrease the aggregation process in the presence of membrane models and to strongly delay the membrane-leakage induced by hIAPP. More generally, this work provides the proof of concept that our rational design is a versatile and relevant strategy for developing efficient and selective inhibitors of aggregation of amyloidogenic proteins.

Dataset Information

Multivalent Polymer-Peptide Conjugates-A General Platform for Inhibiting Amyloid Beta Peptide Aggregation.

Publications

Multivalent Polymer-Peptide Conjugates-A General Platform for Inhibiting Amyloid Beta Peptide Aggregation.

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