The Angiotensin Metabolite His-Leu Is a Strong Copper Chelator Forming Highly Redox Active Species DOI Creative Commons
Nina E. Wezynfeld, Dobromiła Sudzik, Aleksandra Tobolska

et al.

Inorganic Chemistry, Journal Year: 2024, Volume and Issue: 63(26), P. 12268 - 12280

Published: June 15, 2024

His-Leu is a hydrolytic byproduct of angiotensin metabolism, whose concentration in the bloodstream could be at least micromolar. This encouraged us to investigate its Cu(II) binding properties and concomitant redox reactivity. The constants were derived from isothermal titration calorimetry potentiometry, while identities structures complexes obtained ultraviolet-visible, circular dichroism, room-temperature electronic paramagnetic resonance spectroscopies. Four types Cu(II)/His-Leu detected. histamine-like prevail low pH. At neutral mildly alkaline pH Cu(II):His-Leu ratios, they are superseded by diglycine-like involving deprotonated peptide nitrogen. His-Leu:Cu(II) ratios ≥2, bis-complexes formed instead. Above 10.5, complex containing equatorially coordinated hydroxyl group predominates all tested. also strongly active, as demonstrated voltammetric studies ascorbate oxidation assay. Finally, numeric competition simulations with human serum albumin, glycyl-histydyl-lysine, histidine revealed that might part low-molecular weight pool blood if abundance >10 μM. These results yield further questions, such biological relevance ternary His-Leu.

Language: Английский

The metal ion hypothesis of Alzheimer’s disease and the anti-neuroinflammatory effect of metal chelators DOI
Lilin Chen,

Yonggang Fan,

Lingxiao Zhao

et al.

Bioorganic Chemistry, Journal Year: 2022, Volume and Issue: 131, P. 106301 - 106301

Published: Nov. 25, 2022

Language: Английский

Citations

115
Targeting misfolding and aggregation of the amyloid-β peptide and mutant p53 protein using multifunctional molecules DOI

Lauryn Grcic,

Grace Leech,

Kalvin Kwan

et al.

Chemical Communications, Journal Year: 2024, Volume and Issue: 60(11), P. 1372 - 1388

Published: Jan. 1, 2024

We highlight recent advances in the development of multifunctional molecules designed to limit misfolding and aggregation intrinsically disordered biomolecules, with a focus on amyloid-beta peptide AD mutant p53 protein cancer.

Language: Английский

Citations

7
Redox processes in Cu-binding proteins: the “in-between” states in intrinsically disordered peptides DOI Creative Commons
Enrico Falcone, Christelle Hureau

Chemical Society Reviews, Journal Year: 2023, Volume and Issue: 52(19), P. 6595 - 6600

Published: Jan. 1, 2023

The “in-between” states (IBS) in copper bound to intrinsically disordered proteins (IDPs) are accessible due the flexibility of IDPs and fast exchange between coordination sites, they account for formation reactive oxygen species (ROS).

Language: Английский

Citations

14
Modification of amyloid-beta peptide aggregation via photoactivation of strained Ru(ii) polypyridyl complexes DOI Creative Commons

Janaina C. Bataglioli,

Luiza M. F. Gomes,

Camille Maunoir

et al.

Chemical Science, Journal Year: 2021, Volume and Issue: 12(21), P. 7510 - 7520

Published: Jan. 1, 2021

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive and irreversible damage to the brain. One of hallmarks presence both soluble insoluble aggregates amyloid beta (Aβ) peptide in brain, these are considered central progression. Thus, development small molecules capable modulating Aβ aggregation may provide critical insight into pathophysiology AD. In this work we investigate how photoactivation three distorted Ru(ii) polypyridyl complexes (Ru1-3) alters profile peptide. Photoactivation Ru1-3 results loss 6,6'-dimethyl-2,2'-bipyridyl (6,6'-dmb) ligand, affording cis-exchangeable coordination sites for binding Both Ru1 Ru2 contain an extended planar imidazo[4,5-f][1,10]phenanthroline as compared 2,2'-bipyridine ligand Ru3, show that phenanthroline promotes covalent His residues, addition, leads pronounced effect on immediately after photoactivation. Interestingly, all resulted similar aggregate size distribution at 24 h, forming amorphous significant fibril formation alone. pre-formed Aβ1-42 fibrils change morphology, with large activation. Our either monomeric or fibrillar common endpoint, Ru incorporating accelerating process thereby limiting oligomeric species initial stages reported considerable toxicity.

Language: Английский

Citations

25
The reactivity of copper complexes with neuronal peptides promoted by catecholamines and its impact on neurodegeneration DOI
Chiara Bacchella, Simone Dell’Acqua, Stefania Nicolis

et al.

Coordination Chemistry Reviews, Journal Year: 2022, Volume and Issue: 471, P. 214756 - 214756

Published: Aug. 11, 2022

Language: Английский

Citations

17
Development of Cu(ii)-specific peptide shuttles capable of preventing Cu–amyloid beta toxicity and importing bioavailable Cu into cells DOI Creative Commons
Michael Okafor, Paulina González,

Pascale Ronot

et al.

Chemical Science, Journal Year: 2022, Volume and Issue: 13(40), P. 11829 - 11840

Published: Jan. 1, 2022

Copper (Cu) in its ionic forms is an essential element for mammals and homeostasis tightly controlled. Accordingly, Cu-dyshomeostasis can be lethal as the case well-established genetic Wilson's Menkes diseases. In Alzheimer's disease (AD), Cu-accumulation occurs amyloid plaques, where it bound to amyloid-beta peptide (Aβ). vitro, Cu-Aβ competent catalyze production of reactive oxygen species (ROS) presence ascorbate under aerobic conditions, hence believed contribute oxidative stress AD. Several molecules that recover extracellular Cu from Aβ transport back into cells with beneficial effects cell culture transgenic AD models were identified. However, all Cu-shuttles currently available are not satisfactory due various potential limitations including ion selectivity toxicity. Hence, we designed a novel peptide-based shuttle following properties: (i) contains Cu(ii)-binding motif very selective Cu(ii) over other metal ions; (ii) tagged fluorophore sensitive release; (iii) made platform, which versatile add new functions. The work presented here reports on characterization AKH-αR5W4NBD, able ions selectively PC12 imported appeared bioavailable, likely via reductive release induced by glutathione. Moreover, AKH-αR5W4NBD was withdraw Aβ1-16 consequently inhibited based related could valuable tool Cu-transport suitable mechanistic studies culture, applications restoring Cu-homeostasis Cu-related diseases such

Language: Английский

Citations

16
Nanostructure and dynamics of N-truncated copper amyloid-β peptides from advanced X-ray absorption fine structure DOI Creative Commons
Ruwini S. K. Ekanayake, Victor A. Streltsov, Stephen P. Best

et al.

IUCrJ, Journal Year: 2024, Volume and Issue: 11(3), P. 325 - 346

Published: April 11, 2024

An X-ray absorption spectroscopy (XAS) electrochemical cell was used to collect high-quality XAS measurements of N-truncated Cu:amyloid-β (Cu:Aβ) samples under near-physiological conditions. Cu:Aβ peptide complexes contribute oxidative stress and neurotoxicity in Alzheimer's patients' brains. However, the redox properties copper different Aβ sequences are inconsistent. Therefore, geometry binding sites for 4–8/12/16 determined using novel advanced extended fine structure (EXAFS) analysis. This enables these peptides perform cycles a manner that might produce toxicity human Fluorescence were corrected systematic errors including defective-pixel data, monochromator glitches dispersion pixel spectra. Experimental uncertainties at each data point measured explicitly from point-wise variance measurements. The copper-binding environments precisely by fitting with propagated experimental uncertainties, analysis hypothesis testing, providing mechanism pursue many similarly complex questions bioscience. low-temperature here determine Cu II is bound first amino acids high-affinity amino-terminal nickel (ATCUN) motif an oxygen tetragonal pyramid peptides. Room-temperature electrochemical-cell observe metal reduction 4–16 peptide. Robust investigations provide structural details very bis -His water quasi-tetrahedral geometry. Oxidized 4–12/16 imply both III accommodated ATCUN-like site. Hypotheses I , geometries proven disproven statistical F tests. Structural parameters accuracy some tenfold better than literature claims past work. A new protocol also developed EXAFS monitoring radiation damage. gives template biosystems.

Language: Английский

Citations

3
Intelligent Screening of Functional Small Molecules for Targeting Metal-Induced Protein Aggregation DOI
Cong Xiao,

Jiaqi Shi,

Jingyu Yan

et al.

Analytical Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: May 6, 2025

Screening small-molecule drugs to suppress protein aggregation and the production of reactive oxygen species (ROS) is one primary directions for drug development in neurodegenerative diseases (NDs). However, current methods often have difficulty striking a balance between accuracy simplicity. In this work, we constructed active peptide interfaces intelligently screen potential metal-induced with logic network. Taking β-amyloid (Aβ), which closely related Alzheimer's disease (AD), as an example, covalently connected Aβ onto gold electrode surface characterized state induced by copper ions (Cu(II)) through electrochemical impedance spectroscopy (EIS). The formed Aβ-Cu(II) complex were also used study catalytic ROS ameliorative effect on oxidative stress ultraviolet (UV) spectrum ascorbic acid (AA). By constructing comparator network using EIS UV signals, small molecules targeting aggregations could be classified into 4 different types effects. Transmission electron microscopy (TEM), cytotoxicity, assays verify reliability classification. corresponding results α-synuclein (α-Syn) instead indicated that intelligent screening platform might provide general route NDs' screening.

Language: Английский

Citations

0
Redox behaviour of Cu-Aβ(4-16) complexes related to Alzheimer's Disease DOI
Magdalena Z. Wiloch, Steven Linfield, Natalia Baran

et al.

Electrochimica Acta, Journal Year: 2024, Volume and Issue: 485, P. 144089 - 144089

Published: March 13, 2024

Language: Английский

Citations

2
The effect of histidine, histamine, and imidazole on electrochemical properties of Cu(II) complexes of Aβ peptides containing His-2 and His-3 motifs DOI Creative Commons
Aleksandra Tobolska, Agnieszka Jabłońska,

Aleksandra Suwińska

et al.

Dalton Transactions, Journal Year: 2024, Volume and Issue: 53(36), P. 15359 - 15371

Published: Jan. 1, 2024

Low molecular-weight substances may promote the Cu( ii )/Cu( i ) cycle for ions bound to N-truncated Aβ by (1) removing from )/Aβ complexes, (2) changing coordination, and (3) facilitating reoxidation.

Language: Английский

Citations

2