Designed Amyloid β Peptide Fibril—A Tool for High‐Throughput Screening of Fibril Inhibitors

Dolphin, Gunnar T.; Ouberaï, Myriam; Dumy, Pascal; Garcia, Julian

doi:10.1002/cmdc.200700103

Cited by 19 publications

(32 citation statements)

References 53 publications

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“…The structures of the compounds are shown in Table 1 and were selected based on similarity to existing anti-Aβ compounds, as well as grouped into single and double ring structures. For example the following structures were similar to existing anti-amyloids: nialamide ≈ nordihydroguaiaretic [54], isonicotinic acid hydrazide and 4-amino benzhydrazide ≈ o-vanillin [55], 1,1′-diphenylhydrazine hydrochloride ≈ 4,4′-dihydroxybenzophenone [54], hydralazine ≈ napthoquinone and juglone [55], and finally indole-3- acetic hydrazide ≈ similar substructure to azure C [55] and myrecetin [54]. Additionally, while hydrazides are reactive compounds, they have been and can be used as drugs.…”

Section: Resultsmentioning

confidence: 99%

Hydralazine Modifies Aβ Fibril Formation and Prevents Modification by Lipids in Vitro

et al. 2010

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Lipid oxidative damage and Amyloid β (Aβ) misfolding contribute to Alzheimer's disease (AD) pathology. Thus, the prevention of oxidative damage and Aβ misfolding are attractive targets for drug discovery. At present, no AD drugs approved by the Food and Drug Administration (FDA) prevent or halt disease progression. Hydralazine, a smooth muscle relaxant, is a potential drug candidate for AD drug therapy as it reduces Aβ production and prevents oxidative damage via its antioxidant hydrazide group. We evaluated the efficacy of hydralazine, and related hydrazides, in reducing 1) Aβ misfolding and 2) Aβ protein modification by the reactive lipid 4-hydroxy-2-nonenal (HNE) using transmission electron microscopy and Western blotting. While hydralazine did not prevent Aβ aggregation as measured using the protease protection assay, there were more oligomeric species observed by electron microscopy. Hydralazine prevented lipid modification of Aβ, and Aβ was used as proxies for classes of proteins which either misfold or are modified by HNE. All of the other hydrazides prevented lipid modification of Aβ, and also did not prevent Aβ aggregation. Surprisingly, a few of the compounds, carbazochrome and niclosamide, appeared to augment Aβ formation. Thus, hydrazides reduced lipid oxidative damage and hydralazine additionally reduced Aβ misfolding. While hydralazine would require specific chemical modifications for use as an AD therapeutic itself -(to improve blood brain barrier permeability, reduce vasoactive side effects, and optimization for amyloid inhibition)-this study suggests its potential merit for further AD drug development. KeywordsAmyloid-β; free radicals; oxidative stress; Alzheimer's disease; hydrazide; hydralazine; 4-hydroxy-2-nonenal Amyloid β protein (Aβ), which misfolds and accumulates in Alzheimer's disease (AD) brains, is central to the "amyloid hypothesis" where Aβ causes AD pathology [1,2]. This toxicity is in part due to increased oxidative damage [3][4][5][6][7][8] and the toxicity of oligomeric species of Aβ [9]. Indeed, Aβ may play a direct role in this oxidative damage as it directly oxidizes many substrates, including lipids [10][11][12][13][14][15]. Additionally, amyloid plaques, of which Aβ is the major component [16,17] and contain transition metals [18][19][20][21][22][23][24] as well as are competent for generating oxidative stress [18,25,26]. The oxidation products generated, such as H 2 O 2 and reactive lipid oxidation products such as 4-hydroxy-2-nonenal (HNE), are likely mediators of toxicity in this disease. Identification of compounds that can prevent these two pathological features of AD, oxidative damage and protein misfolding, could provide the basis for future drugs for AD. Hydralazine was selected as it is an excellent scavenger of reactive lipid oxidation products, such as acrolein and HNE, and also prevents the lipid modification and crosslinking of proteins [27][28][29][30][31][32][33][34][35]. In addition to reducing reactive oxygen species and lipid peroxidation, hydralaz...

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Section: Resultsmentioning

confidence: 99%

Hydralazine Modifies Aβ Fibril Formation and Prevents Modification by Lipids in Vitro

et al. 2010

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“…As noted, these findings confirm that Aβ42 fusions expressed in plant cells can be used to detect small molecule and phytochemical inhibitors effective in preventing the misfolding/aggregation of Aβ42 peptides, and provide support for the use of this system for drug screening. A number of screening methods have been developed to detect Aβ aggregation inhibitors [47][48][49][50]. Most use turbidity or thioflavin T-binding assays to assess molecules that interfere with the formation of fibrillar aggregates from pure synthetic Aβ peptides.…”

Section: Discussionmentioning

confidence: 99%

A plant cell-based system that predicts aβ42 misfolding: Potential as a drug discovery tool for Alzheimer's disease

Zhao

Zeng

Kermode

2012

Molecular Genetics and Metabolism

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“…However, AFM images of the Ab 1-40 assays showed no inhibition of fibril formation compared to the control (Figure 4 A and B). Considering that filter-effects can be ruled out for 6 and 7 because they do not absorb at the wavelengths of fluorescence excitation or emission, [26] fluorescence inhibition is probably caused by direct competition against the fluorescent reporter ThT for binding to the fibrils, a typical feature of polyphenolic compounds. [26] The same effects were observed with the phenolic bis-oximes 10, 11, 14 with IC 50 values in the 10-30 mm range, but no effective inhibition of fibril formation when tested by AFM.…”

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confidence: 99%

“…In summary, screening for inhibition of amyloid fibril formation using our recently reported microtiterplate fluorescence assay [26] was implemented for the first time to discover new inhibitors in a library of oxime oligomers. Investigation of initial hits by AFM revealed that the smaller oxime and dioxime hits inhibited fluorescence without blocking amyloid formation, presumably by direct competition with the fluorescence label ThT for binding to the fibrils.…”

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confidence: 99%

“…[18,24] We recently reported an efficient high-throughput screen (HTS) for inhibitors of amyloid fibril formation using an engineered synthetic fibril building block (Ab 16-37 Y 20 K 22 K 24 ) 4 displaying controllable kinetics of fibril formation. [25,26] The assay uses fluorescence detection of the characteristic cross-b sheet structure of amyloid fibrils by the dye thioflavin T (ThT). [27][28][29] In our effort to discover new inhibitors of Ab fibril formation, we A C H T U N G T R E N N U N G applied this HTS to a library of oxime oligomers prepared by an iterative two-step procedure for the oligomerization of hydroxy-aromatic aldehydes (Scheme 1), [30][31][32] and discovered of two novel inhibitors of Ab fibril formation, 19 and 22…”

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confidence: 99%

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Phenolic Oxime Oligomers Inhibit Alzheimer's Amyloid Fibril Formation and Disaggregate Fibrils In Vitro

Dolphin¹,

Renaudet²,

Ouberaï³

et al. 2009

ChemBioChem

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Designed Amyloid β Peptide Fibril—A Tool for High‐Throughput Screening of Fibril Inhibitors

Cited by 19 publications

References 53 publications

Hydralazine Modifies Aβ Fibril Formation and Prevents Modification by Lipids in Vitro

Hydralazine Modifies Aβ Fibril Formation and Prevents Modification by Lipids in Vitro

A plant cell-based system that predicts aβ42 misfolding: Potential as a drug discovery tool for Alzheimer's disease

Phenolic Oxime Oligomers Inhibit Alzheimer's Amyloid Fibril Formation and Disaggregate Fibrils In Vitro

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