α‐Synuclein as a Target for Metallo‐Anti‐Neurodegenerative Agents

Cao, Kaiming; Yang, Zhu; Hou, Zhuanghao; Liu, Manman; Yang, Yanyan; Hu, Hongze; Dai, Yi; Wang, Yu; Yuan, Siming; Huang, Guangming; Mei, Jiaming; Sadler, Peter J.; Liu, Yangzhong

doi:10.1002/anie.202215360

Cited by 8 publications

(7 citation statements)

References 52 publications

(43 reference statements)

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“…Similarly, heterodinuclear complexes containing both Pt(II) and Ru(II) metal ions bridged by 2,3-bis(2-pyridyl)benzoquinoxaline ligands exhibit a different mechanism of action where the inhibition of Aβ aggregation is due to Aβ 1–42 conformational variations that force it to remain in the monomeric form . Very recently, it has been shown that NAMI-A has a dual inhibitory effect on both aggregation and membrane interaction of α-synuclein (α-syn) associated with Parkinson’s disease (PD) . This complex abolishes the cytotoxicity of α-syn toward neuronal cells and mitigates neurodegeneration and motor impairments in a rat model of PD.…”

Section: Introductionmentioning

confidence: 99%

A Diruthenium Metallodrug as a Potent Inhibitor of Amyloid-β Aggregation: Synergism of Mechanisms of Action

La Manna,

Di Natale,

Panzetta

et al. 2023

Inorg. Chem.

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The physical and chemical properties of paddlewheel diruthenium compounds are highly dependent on the nature of the ligands surrounding the bimetallic core. Herein, we compare the ability of two diruthenium compounds, [Ru 2 Cl(D-p-FPhF)- 2), to act as inhibitors of amyloid aggregation of the Aβ 1−42 peptide and its peculiar fragments, Aβ 1−16 and Aβ 21−40 . A wide range of biophysical techniques has been used to determine the inhibition capacity against aggregation and the possible mechanism of action of these compounds (Thioflavin T fluorescence and autofluorescence assays, UV−vis absorption spectroscopy, circular dichroism, nuclear magnetic resonance, mass spectrometry, and electron scanning microscopy). Data show that the most effective inhibitory effect is shown for compound 1. This compound inhibits fiber formation and completely abolishes the cytotoxicity of Aβ 1−42 . The antiaggregatory capacity of this complex can be explained by a binding mechanism of the dimetallic units to the peptide chain along with π−π interactions between the formamidinate ligand and the aromatic side chains. The results suggest the potential use of paddlewheel diruthenium complexes as neurodrugs and confirm the importance of the steric and charge effects on the properties of diruthenium compounds.

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Section: Introductionmentioning

confidence: 99%

A Diruthenium Metallodrug as a Potent Inhibitor of Amyloid-β Aggregation: Synergism of Mechanisms of Action

La Manna,

Di Natale,

Panzetta

et al. 2023

Inorg. Chem.

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“…Protein misfolding is a process in which protein fails to fold into its native functional conformation and will lead to protein aggregates in cells . A growing number of studies have demonstrated that the abnormal aggregation of proteins is associated with many common neurogenerative diseases, , such as Alzheimer’s disease, , Parkinson’s disease, , and Huntington’s disease . Canonically, protein aggregation is closely related to organelles such as mitochondria and lysosome .…”

Section: Introductionmentioning

confidence: 99%

Versatile Fluorescence Lifetime-Based Copper Probe to Quantify Mitochondrial Membrane Potential and Reveal Its Interaction with Protein Aggregation

Xiao,

Wan,

Gao

et al. 2024

Anal. Chem.

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Mitochondria play a crucial role in maintaining cellular homeostasis, and the depolarization of mitochondrial membrane potential (MMP) is an important signal of apoptosis. Additionally, protein misfolding and aggregation are closely related to diseases including neurodegenerative diseases, diabetes, and cancers. However, the interaction between MMP changes and disease-related protein aggregation was rarely studied. Herein, we report a novel "turn-on" fluorescent probe MitoRhB that specifically targets to mitochondria for Cu 2+ detection in situ. The fluorescence lifetime (τ) of MitoRhB exhibits a positive correlation with MMP changes, allowing us to quantitatively determine the relative MMP during SOD1 (A4 V) protein aggregation. Finally, we found that (1) the increasing concentrations of copper will accelerate the depolarization of mitochondria and reduce MMP; (2) the depolarization of mitochondria can intensify the degree of protein aggregation, suggesting a new routine of copper-induced cell death mediated through abnormal MMP depolarization and protein aggregation.

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“…The IDP of this article’s interest, alpha-synuclein ( α S) has remained an important drug-target 24–27 owing to its long-rooted association with neurodegenerative diseases. Often, the early aggregation stages of α S into small oligomers is implicated in the causation of Parkinson’s disease 28–31 and a potential therapeutic strategy has been the stabilization of α S in soluble monomeric form.…”

Section: Introductionmentioning

confidence: 99%

An Integrated Machine Learning Approach Delineates an Entropic Expansion Mechanism for the Binding of a Small Molecule toα-Synuclein

Menon,

Adhikari,

Mondal

2024

Preprint

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Aberrant misfolding and progressive aggregation of the intrinsically disordered protein (IDP), alpha-synuclein (alphaS), is associated with the aetiology of several neurodegenerative diseases. However, the discovery of potential small-molecules targeting alphaS often hits a bottleneck due to the lack of a designated binding pocket in its structurally heterogeneous ensemble. Here, by integrating Markov State Modelling approach with a deep-learning work-flow namely beta-Variational Autoencoder (beta-VAE), we statistically dissect a large conformational ensemble of alpha in neat water and aqueous solution of fasudil (small molecule of interest) into a set of mutually distinct metastable states. We find that fasudil interacting with &alphaS leads to the formation of significantly higher number of conformational states than that in water, akin to an ensemble-expansion mechanism. The ensembles possess mutually diverse intra-protein contact maps and display strong conformation-dependence in residue-wise interaction with the small molecule. A thermodynamic analysis reveals that fasudil influences the structural repertoire of alphaS by tuning protein backbone entropy, without perturbing entropic ordering of surrounding solvent. Together, the investigation demonstrates the distinctive effect of a drug molecule on an IDP, elucidating entropic modulation and ensemble expansion as a mechanism for conformational changes.

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α‐Synuclein as a Target for Metallo‐Anti‐Neurodegenerative Agents

Cited by 8 publications

References 52 publications

A Diruthenium Metallodrug as a Potent Inhibitor of Amyloid-β Aggregation: Synergism of Mechanisms of Action

A Diruthenium Metallodrug as a Potent Inhibitor of Amyloid-β Aggregation: Synergism of Mechanisms of Action

Versatile Fluorescence Lifetime-Based Copper Probe to Quantify Mitochondrial Membrane Potential and Reveal Its Interaction with Protein Aggregation

An Integrated Machine Learning Approach Delineates an Entropic Expansion Mechanism for the Binding of a Small Molecule toα-Synuclein

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