Molecular chirality mediated amyloid formation on phospholipid surfaces

Wang, Xue; Wang, Cunli; Chu, Huiying; Qin, Haijuan; Wang, Dongdong; Xu, Feifei; Quan, Chunshan; Li, Guohui; Qing, Guangyan

doi:10.1039/d0sc02212h

Cited by 20 publications

(24 citation statements)

References 81 publications

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“…The ability of PCu to inhibit the aggregation of Aβ1-42-Cu(II) was monitored using a ThT fluorescence assay at 0.5, 2 and 24 h. As shown in Figure 3A, PCu inhibited the formation of Aβ1-42-Cu(II) aggregates by about 60% at 2 h, which remained at 60% after 24 h, suggesting that as long as PCu was present, the fluorescence intensity of Aβ1-42 aggregates could be maintained at a low level. In addition, compared with Aβ1-42 alone, the addition of Cu(II) reduced the ThT fluorescence level, suggesting that Cu(II) triggered the formation of partial Aβ1-42 oligomers because ThT selectively binds to amyloid fibrils but does not interact with unstructured Aβ monomers and oligomers [47,48]. Therefore, the ThT fluorescence intensity was not as high as that in the presence of Aβ1-42 alone, which is consistent with previous studies [49,50].…”

Section: Inhibition Of Cu 2+ -Mediated Aβ1-42 Aggregation By Pcu In Vitrosupporting

confidence: 87%

A Novel Cu(II)-Binding Peptide Identified by Phage Display Inhibits Cu2+-Mediated Aβ Aggregation

Zhang

Zhong

et al. 2021

IJMS

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Copper (Cu) has been implicated in the progression of Alzheimer’s disease (AD), and aggregation of Cu and amyloid β peptide (Aβ) are considered key pathological features of AD. Metal chelators are considered to be potential therapeutic agents for AD because of their capacity to reduce metal ion-induced Aβ aggregation through the regulation of metal ion distribution. Here, we used phage display technology to screen, synthesize, and evaluate a novel Cu(II)-binding peptide that specifically blocked Cu-triggered Aβ aggregation. The Cu(II)-binding peptide (S-A-Q-I-A-P-H, PCu) identified from the phage display heptapeptide library was used to explore the mechanism of PCu inhibition of Cu2+-mediated Aβ aggregation and Aβ production. In vitro experiments revealed that PCu directly inhibited Cu2+-mediated Aβ aggregation and regulated copper levels to reduce biological toxicity. Furthermore, PCu reduced the production of Aβ by inhibiting Cu2+-induced BACE1 expression and improving Cu(II)-mediated cell oxidative damage. Cell culture experiments further demonstrated that PCu had relatively low toxicity. This Cu(II)-binding peptide that we have identified using phage display technology provides a potential therapeutic approach to prevent or treat AD.

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Section: Inhibition Of Cu 2+ -Mediated Aβ1-42 Aggregation By Pcu In Vitrosupporting

confidence: 87%

A Novel Cu(II)-Binding Peptide Identified by Phage Display Inhibits Cu2+-Mediated Aβ Aggregation

Zhang

Zhong

et al. 2021

IJMS

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“…Therefore, prevention, inhibition and elimination of amyloid deposition in the brain of AD are promising. Aβ fibril formation is a self-assembly process that initiates with a lag phase (oligomer/critical nucleus formation), followed by elongation (oligomer polymerization) and fibril maturation 64 - 66 , and these different Aβ conformations have also been used as selection baits for phage display technology.…”

Section: Phage Display Technology-based Ad Therapymentioning

confidence: 99%

Phage display derived peptides for Alzheimer's disease therapy and diagnosis

Zhang¹,

Zhang²,

Gao³

et al. 2022

Theranostics

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Alzheimer's disease (AD) is an incurable and fatal progressive neurodegenerative disorder associated with memory and cognition impairment. AD is one of the top medical care concerns across the world with a projected economic burden of $2 trillion by 2030. To date, however, there remains no effective disease-modifying therapy available. It is more important than ever to reveal novel therapeutic approaches. Peptide-based biotherapeutics has been a great potential strategy attributed to their distinct and superior biochemical characteristics, such as reproducible chemical synthesis and modification, rapid cell and tissue permeability, and fast blood clearance. Phage display, one of today's most powerful platforms, allows selection and identification of suitable peptide drug candidates with high affinities and specificity toward target, demonstrating the potential to overcome challenges and limitations in AD diagnosis/treatment. We aim to provide the first comprehensive review to summarize the status in this research direction. The biological overview of phage display is described, including basic biology of the phage vectors and construction principle of phage library, biopanning procedure, mirror image phage display, and various binding affinity evaluation approaches. Further, the applications of phage display in AD therapy, targeted drug delivery, and early detection are presented. Finally, we discuss the current challenges and offer a future outlook for further advancing the potential application of phage display on AD and other neurodegenerative diseases.

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“…[63] The Qing group demonstrated the kinetics of formation of Aβ aggregates using chiral phospholipid scaffolds. [64] To add a chiral center to DPPE headgroups, L-or D-aspartic acid (Asp) monomers were added to the phosphate moiety and liposomes were formed. Asp monomers were chosen because racemization of Asp in Aβ by isomerases has been shown to affect the formation of fibrils.…”

Section: Cell-damaging Peptidesmentioning

confidence: 99%

“…However, the cells which were cocultured with 1 : 1 DPPE and D-Asp-DPPE liposomes had a significant increase in neuronal cell viability, the LÀ Aβ aggregated less. [64] These liposomes generated a successful method of reducing LÀ Aβ nucleation in neuronal cells.…”

Section: Cell-damaging Peptidesmentioning

confidence: 99%

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Probing the Role of Chirality in Phospholipid Membranes

2021

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Nucleotides, amino acids, sugars, and lipids are almost ubiquitously homochiral within individual cells on Earth. While oligonucleotides and proteins exist as one natural chirality throughout the tree of life, two stereoisomers of phospholipids have separately emerged in archaea and bacteria, an evolutionary divergence known as "the lipid divide". Within this review, we focus on the emergence of phospholipid homochirality and compare the stability of synthetic homochiral and heterochiral membranes in vitro. We discuss chemical probes designed to study the stereospecific interactions of lipid membranes in vitro. Overall, we aim to highlight studies that help elucidate the determinants of stereospecific interactions between lipids, peptides, and small molecule ligands. Continued work in understanding the drivers of favorable interactions between chiral molecules and biological membranes will lead to the design of increasingly selective chemical tools for bioorthogonal labeling of lipid membranes and safer membrane-associating pharmaceuticals.

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Molecular chirality mediated amyloid formation on phospholipid surfaces

Abstract:
A remarkable inhibition effect and chiral discrimination are observed when the amyloid peptide aggregates on chiral phospholipid surfaces.

Cited by 20 publications

References 81 publications

A Novel Cu(II)-Binding Peptide Identified by Phage Display Inhibits Cu2+-Mediated Aβ Aggregation

A Novel Cu(II)-Binding Peptide Identified by Phage Display Inhibits Cu2+-Mediated Aβ Aggregation

Phage display derived peptides for Alzheimer's disease therapy and diagnosis

Probing the Role of Chirality in Phospholipid Membranes

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Molecular chirality mediated amyloid formation on phospholipid surfaces

Abstract: A remarkable inhibition effect and chiral discrimination are observed when the amyloid peptide aggregates on chiral phospholipid surfaces.

Cited by 20 publications

References 81 publications

A Novel Cu(II)-Binding Peptide Identified by Phage Display Inhibits Cu2+-Mediated Aβ Aggregation

A Novel Cu(II)-Binding Peptide Identified by Phage Display Inhibits Cu2+-Mediated Aβ Aggregation

Phage display derived peptides for Alzheimer's disease therapy and diagnosis

Probing the Role of Chirality in Phospholipid Membranes

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Product

Resources

About

Abstract:
A remarkable inhibition effect and chiral discrimination are observed when the amyloid peptide aggregates on chiral phospholipid surfaces.