Binuclear ruthenium complexes inhibit the fibril formation of human islet amyloid polypeptide

Gong, Gehui; Du, Weihong

doi:10.1039/c6ra28107a

Cited by 22 publications

(7 citation statements)

References 66 publications

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“…Hence, the aromatic residues were not intensively influenced, suggesting that the binding site of artemisinin with the peptide was not very close to these aromatic residues. Due to the limitation of compound solubility and the signal interference from the solvent, we could not carry out a circular dichroism study to clarify the peptide conformation change as we did previously. − Nevertheless, similar results of morphological change elucidated that the β-sheet component should be effectively decreased.…”

Section: Resultsmentioning

confidence: 90%

Regulation of Artemisinin and Its Derivatives on the Assembly Behavior and Cytotoxicity of Amyloid Polypeptides hIAPP and Aβ

Zhao

Huang

et al. 2019

ACS Chem. Neurosci.

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The misfolding and aggregation of human islet amyloid polypeptide (hIAPP) and amyloid-β (Aβ) protein are closely associated with type 2 diabetes mellitus (T2DM) and Alzheimer’s disease, respectively. Inhibitors of amyloid peptides include short peptides, aromatic organic molecules, nanoparticles, and even metal compounds. Sesquiterpenoid artemisinins are widely used in anti-malaria treatments, and they may modulate glucose homeostasis against diabetes. However, the antidiabetic mechanism of these compounds remains unclear. In this work, four compounds, namely, artemisinin (1), dihydroartemisinin (2), artesunate (3), and artemether (4), were exploited to inhibit the assembly behavior of hIAPP and compared with that of Aβ. Although structurally distinct from other aromatic inhibitors of amyloid peptides, these sesquiterpenoids effectively altered the two peptides’ fibril morphologies and disaggregated the mature fibrils mostly to the monomers. The interaction of artemisinins with the two peptides demonstrated a spontaneous, exothermic, and entropy-driven binding process predominantly through hydrophobic and hydrogen bonding interactions. Moreover, they reversed cytotoxicity and membrane leakage by reducing peptides’ oligomerization. The results suggested that these compounds had better inhibition and disaggregation capability against hIAPP than against Aβ. Furthermore, the effects of these compounds’ structural modification on the amyloid fibril formation of the two peptides were observed. The molecular screening offered a new perspective for artemisinins as promising inhibitors against amyloidosis related diseases.

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Section: Resultsmentioning

confidence: 90%

Regulation of Artemisinin and Its Derivatives on the Assembly Behavior and Cytotoxicity of Amyloid Polypeptides hIAPP and Aβ

Zhao

Huang

et al. 2019

ACS Chem. Neurosci.

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“…Metallodrugs are unique and therapeutic agents that exert their bioactivity mostly through their coordination at the metal center and additional intermolecular interactions from the attached ligand(s) . Recent examples are increasingly frequent in the literature, concerning metal complexes as antiaggregating agents of proteins involved in neurodegenerative diseases (NDDs). − However, in drug-discovery related to NDDs, different approaches are generally employed; the most explored ones consist in the identification of inhibitors of amyloid formation to suppress toxic intermediates ,− and in the search of agents able to accelerate the kinetics of conversion of toxic oligomers into fibers …”

Section: Discussionmentioning

confidence: 99%

Metal-Complexes Bearing Releasable CO Differently Modulate Amyloid Aggregation

et al. 2023

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Neurodegenerative diseases are often associated with an uncontrolled amyloid aggregation. Hence, many studies are oriented to discover new compounds that are able to modulate self-recognition mechanisms of proteins involved in the development of these pathologies. Herein, three metal-complexes able to release carbon monoxide (CORMs) were analyzed for their ability to affect the self-aggregation of the amyloidogenic fragment of nucleophosmin 1, corresponding to the second helix of the three-helix bundle located in the C-terminal domain of the protein, i.e., NPM1264–277, peptide. These complexes were two cymantrenes coordinated to the nucleobase adenine (Cym-Ade) and to the antibiotic ciprofloxacin (Cym-Cipro) and a Re(I)-compound containing 1,10-phenanthroline and 3-CCCH2NHCOCH2CH2-6-bromo-chromone as ligands (Re-Flavo). Thioflavin T (ThT) assay, UV–vis absorption and fluorescence spectroscopies, scanning electron microscopy (SEM), and electrospray ionization mass spectrometry (ESI-MS) indicated that the three compounds have different effects on the peptide aggregation. Cym-Ade and Cym-Cipro act as aggregating agents. Cym-Ade induces the formation of NPM1264–277 fibers longer and stiffer than that formed by NPM1264–277 alone; irradiation of complexes speeds the formation of fibers that are more flexible and thicker than those found without irradiation. Cym-Cipro induces the formation of longer fibers, although slightly thinner in diameter. Conversely, Re-Flavo acts as an antiaggregating agent. Overall, these results indicate that metal-based CORMs with diverse structural features can have a different effect on the formation of amyloid fibers. A proper choice of ligands attached to metal can allow the development of metal-based drugs with potential application as antiamyloidogenic agents.

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“…The complex [Ru(bipy)(met) 2 ]·3H 2 O (met = methionine) inhibits the fibril formation of hIAPP and depolymerizes mature fibrils [ 20 ]. Binuclear Ru complexes are able to interfere with hIAPP aggregation causing the formation of nanometric particles with reduced β-sheet content and cytotoxicity, exhibiting a greater affinity with respect to the corresponding mononuclear Ru complexes, likely due to synergic contribution of the second center acting as promising metallodrugs in the field of T2DM (Type 2 Diabetes Mellitus) [ 21 ]. A similar synergistic effect was shown by heterobimetallic Ru(II)−Au(I) complexes bearing different spacer lengths (4–8 polyethylene glycol units) able to bind to a fragment of the amyloid β 1−16 in accordance with the binding abilities of parent drugs, RAPTA-C [ 22 ] and auranofin [ 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Modulation of Amyloidogenic Peptide Aggregation by Photoactivatable CO-Releasing Ruthenium(II) Complexes

et al. 2020

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Three Ru(II)-based CO-releasing molecules featuring bidentate benzimidazole and terpyridine derivatives as ligands were investigated for their ability to modulate the aggregation process of the second helix of the C-terminal domain of nucleophosmin 1, namely nucleophosmin 1 (NPM1)264–277, a model amyloidogenic system, before and after irradiation at 365 nm. Thioflavin T (ThT) binding assays and UV/Vis absorption spectra indicate that binding of the compounds to the peptide inhibits its aggregation and that the inhibitory effect increases upon irradiation (half maximal effective concentration (EC50) values in the high micromolar range). Electrospray ionization mass spectrometry data of the peptide in the presence of one of these compounds confirm that the modulation of amyloid aggregation relies on the formation of adducts obtained when the Ru compounds react with the peptide upon releasing of labile ligands, like chloride and carbon monoxide. This mechanism of action explains the subtle different behavior of the three compounds observed in ThT experiments. Overall, data support the hypothesis that metal-based CO releasing molecules can be used to develop metal-based drugs with potential application as anti-amyloidogenic agents.

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Binuclear ruthenium complexes inhibit the fibril formation of human islet amyloid polypeptide

Abstract: Binuclear ruthenium complexes reverse the aggregation of human islet amyloid polypeptide.

Cited by 22 publications

References 66 publications

Regulation of Artemisinin and Its Derivatives on the Assembly Behavior and Cytotoxicity of Amyloid Polypeptides hIAPP and Aβ

Regulation of Artemisinin and Its Derivatives on the Assembly Behavior and Cytotoxicity of Amyloid Polypeptides hIAPP and Aβ

Metal-Complexes Bearing Releasable CO Differently Modulate Amyloid Aggregation

Modulation of Amyloidogenic Peptide Aggregation by Photoactivatable CO-Releasing Ruthenium(II) Complexes

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