Spectrally Tunable Förster Resonance Energy Transfer-Based Biosensors Using Organic Dye Grafting.

Biosensors based on Förster resonance energy transfer (FRET) have revolutionized cellular biology by allowing the direct measurement of biochemical processes . Many genetically encoded sensors make use of fluorescent proteins that are limited in spectral versatility and that allow few ways to change the spectral properties once the construct has been created. In this work, we developed genetically encoded FRET biosensors based on the chemigenetic SNAP and HaloTag domains combined with matching organic fluorophores.

Unexpected Trends in Copper Removal from Aβ Peptide: When Less Ligand Is Better and Zn Helps.

Cu, Zn, and amyloid-β (Aβ) peptides play an important role in the etiology of Alzheimer's disease (AD). Their interaction indeed modifies the self-assembly propensity of the peptide that is at the origin of the deposition of insoluble peptide aggregates in the amyloid plaque, a hallmark found in AD brains. Another even more important fallout of the Cu binding to Aβ peptide is the formation of reactive oxygen species (ROS) that contributes to the overall oxidative stress detected in the disease and is due to the redox ability of the Cu ions.

An easy-to-implement combinatorial approach involving an activity-based assay for the discovery of a peptidyl copper complex mimicking superoxide dismutase.

A combinatorial approach using a one-bead-one-compound method and a screening based on a SOD-activity assay was set up for the discovery of an efficient peptidyl copper complex. The complex exhibited good stability constants, suitable redox potentials and excellent intrinsic activity. This complex was further assayed in cells for its antioxidant properties and showed beneficial effects when cells were subjected to oxidative stress.

Copper-Targeting Approaches in Alzheimer's Disease: How To Improve the Fallouts Obtained from in Vitro Studies.

According to the amyloid cascade hypothesis, metal ions, mainly Cu and Zn ions, bound to the amyloid-β (Aβ) peptides are implicated in Alzheimer's disease (AD), a widespread neurodegenerative disease. They indeed impact the aggregation pathways of Aβ and are involved in the catalytic generation of reactive oxygen species (ROS) that participate in oxidative stress, while Aβ aggregation and oxidative stress are regarded as two key events in AD etiology. Cu ions due to their redox ability have been considered to be the main potential therapeutic targets in AD.

Kinetics Are Crucial When Targeting Copper Ions to Fight Alzheimer's Disease: An Illustration with Azamacrocyclic Ligands.

Targeting copper ions to either remove or redistribute them is currently viewed as a possible therapeutic strategy in the context of Alzheimer's disease (AD). Thermodynamic parameters, as for instance the copper(II) affinity of the drug candidate or the copper(II) over zinc(II) selectivity, are considered in the design of the drug candidate. In contrast, kinetic factors have been overlooked despite their probable high importance.

A Metallo Pro-Drug to Target Cu in the Context of Alzheimer's Disease.

Alzheimer's disease and oxidative stress are connected. In the present communication, we report the use of a Mn -based superoxide dismutase (SOD) mimic ([Mn (L)] , 1 ) as a pro-drug candidate to target Cu -associated events, namely, Cu -induced formation of reactive oxygen species (ROS) and modulation of the amyloid-β (Aβ) peptide aggregation. Complex 1 is able to remove Cu from Aβ, stop ROS and prevent alteration of Aβ aggregation as would do the corresponding free ligand LH.

Mutual interference of Cu and Zn ions in Alzheimer's disease: perspectives at the molecular level.

While metal ions such as copper and zinc are essential in biology, they are also linked to several amyloid-related diseases, including Alzheimer's disease (AD). Zinc and copper can indeed modify the aggregation pathways of the amyloid-β (Aβ) peptide, the key component encountered in AD. In addition, the redox active copper ions do produce Reactive Oxygen Species (ROS) when bound to the Aβ peptide.

A Trishistidine Pseudopeptide with Ability to Remove Both Cu and Cu from the Amyloid-β Peptide and to Stop the Associated ROS Formation.

The pseudopeptide L, derived from a nitrilotriacetic acid scaffold and functionalized with three histidine moieties, is reminiscent of the amino acid side chains encountered in the Alzheimer's peptide (Aβ). Its synthesis and coordination properties for Cu and Cu are described. L efficiently complex Cu in a square-planar geometry involving three imidazole nitrogen atoms and an amidate-Cu bond.

Link between Affinity and Cu(II) Binding Sites to Amyloid-β Peptides Evaluated by a New Water-Soluble UV-Visible Ratiometric Dye with a Moderate Cu(II) Affinity.

Being able to easily determine the Cu(II) affinity for biomolecules of moderate affinity is important. Such biomolecules include amyloidogenic peptides, such as the well-known amyloid-β peptide involved in Alzheimer's disease. Here, we report the synthesis of a new water-soluble ratiometric Cu(II) dye with a moderate affinity (10 M at pH 7.

How Zn can impede Cu detoxification by chelating agents in Alzheimer's disease: a proof-of-concept study.

The role of Cu and Zn ions in Alzheimer's disease is linked to the consequences of their coordination to the amyloid-β (Aβ) peptide, i.e. to the modulation of Aβ aggregation and to the production of Reactive Oxygen Species (ROS), two central events of the so-called amyloid cascade.

Zinc(II) Binding Site to the Amyloid-β Peptide: Insights from Spectroscopic Studies with a Wide Series of Modified Peptides.

The Zn(II) ion has been linked to Alzheimer's disease (AD) due to its ability to modulate the aggregating properties of the amyloid-β (Aβ) peptide, where Aβ aggregation is a central event in the etiology of the disease. Delineating Zn(II) binding properties to Aβ is thus a prerequisite to better grasp its potential role in AD. Because of (i) the flexibility of the Aβ peptide, (ii) the multiplicity of anchoring sites, and (iii) the silent nature of the Zn(II) ion in most classical spectroscopies, this is a difficult task.

Copper(I) targeting in the Alzheimer's disease context: a first example using the biocompatible PTA ligand.

Copper(I) coordinating ligands in the Alzheimer's disease context have remained unexplored, despite the biological relevance of this redox state of the copper ion. Here, we show that the PTA ligand can remove copper from Aβ, prevent reactive oxygen species production and oligomer formation, two deleterious events in the disease's etiology.