The Amyloid Beta Peptide: A Chemist’s Perspective. Role in Alzheimer’s and Fibrillization

Hamley, Ian W.

doi:10.1021/cr3000994

Cited by 783 publications

(766 citation statements)

References 767 publications

Supporting

Mentioning

751

Contrasting

Unclassified

Order By: Relevance

“…11 The species isolated at the early stages of aggregation were characterized as protobrillar aggregates, comprised of stacks usually formed by two to four b-sheet tapes, 20-70 nm in length and 3 nm in diameter. 12 Therefore, inhibiting the ability of amyloidogenic proteins to adopt a b-sheet conformation would be useful as a way to interfere with the amyloid self-assembly process. Soto 13 demonstrated that incorporation of b-breaker elements into short peptides composed of the recognition sequence of the amyloidogenic protein results in inhibition of amyloid formation.…”

Section: Introductionmentioning

confidence: 99%

A single-residue substitution inhibits fibrillization of Ala-based pentapeptides. A spectroscopic and molecular dynamics investigation

et al. 2014

View full text Add to dashboard Cite

The aggregation properties of two Ala-based pentapeptides were investigated by spectroscopic techniques and molecular dynamics (MD) simulations. The two peptides, both functionalized at the N-terminus with a pyrenyl group, differ in the insertion of an a-aminoisobutyric acid residue at position 4. We showed that this single modification of the homo-peptide sequence inhibits the aggregation of the pentapeptide in aqueous solutions. Atomic force microscopy imaging revealed that the two peptides form mesoscopic aggregates of very different morphologies when deposited on mica. MD experiments showed that the two peptides have a very different propensity to form b-pleated sheet structures, as confirmed by our spectroscopic measurements. The implications of these findings for our understanding of the mechanism leading to the formation of amyloid structures, primary responsible for numerous neurodegenerative diseases, are also discussed.

show abstract

Section: Introductionmentioning

confidence: 99%

A single-residue substitution inhibits fibrillization of Ala-based pentapeptides. A spectroscopic and molecular dynamics investigation

et al. 2014

View full text Add to dashboard Cite

show abstract

“…12 While deposition of Aβ plaques is the hallmark of the disease, the neurotoxicity of Aβ oligomers was shown to be stronger than that of the fibrils. 13,14 Therefore, innovative DMAAD should also possess inhibition properties against Aβ self-association. On these bases, we have developed a new set of multifunctional pharmacological tools that inhibit Aβ self-association and oligomerization, the enzymatic activity of ChEs, and (to a moderate extent) the AChE-induced Aβ aggregation (2a−c, Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Multifunctional Cholinesterase and Amyloid Beta Fibrillization Modulators. Synthesis and Biological Investigation

Butini¹,

Brindisi²,

Brogi³

et al. 2013

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

In order to identify novel Alzheimer's modifying pharmacological tools, we developed bis-tacrines bearing a peptide moiety for specific interference with surface sites of human acetylcholinesterase (hAChE) binding amyloid-beta (Aβ). Accordingly, compounds 2a−c proved to be inhibitors of hAChE catalytic and noncatalytic functions, binding the catalytic and peripheral sites, interfering with Aβ aggregation and with the Aβ self-oligomerization process (2a). Compounds 2a−c in complex with TcAChE span the gorge with the bis-tacrine system, and the peptide moieties bulge outside the gorge in proximity of the peripheral site. These moieties are likely responsible for the observed reduction of hAChE-induced Aβ aggregation since they physically hamper Aβ binding to the enzyme surface. Moreover, 2a was able to significantly interfere with Aβ self-oligomerization, while 2b,c showed improved inhibition of hAChE-induced Aβ aggregation.

show abstract

“…16,17 As part of our research program aimed at discovering and developing novel small-molecules as potential pharmacological tools to study Alzheimer's disease (AD) and …”

mentioning

confidence: 99%

Structure–Activity Relationship Studies of Isomeric 2,4-Diaminoquinazolines on β-Amyloid Aggregation Kinetics

Mohamed

Shakeri

Tin

et al. 2016

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

A library of isomeric 2,4-diaminoquinazoline (DAQ) derivatives were synthesized and evaluated for antiaggregation potential toward Aβ40/42. Structure−activity relationship data identified compound 3k (N 4 -(4-bromobenzyl)-quinazoline-2,4-diamine) with a 4-bromobenzyl substituent as the most potent inhibitor (Aβ40 IC 50 = 80 nM) and was almost 18-fold more potent compared to the reference agent curcumin (Aβ40 IC 50 = 1.5 μM). The corresponding N 2 -isomer 4k (N 2 -(4-bromobenzyl)quinazoline-2,4-diamine) was also able to prevent Aβ aggregation (Aβ40 IC 50 = 1.7 μM). However, compound 4k exhibited superior inhibition of Aβ42 aggregation (Aβ42 IC 50 = 1.7 μM) compared to compound 3k (Aβ42 IC 50 = 14.8 μM) and was ∼1.8-fold more potent compared to curcumin (Aβ42 IC 50 = 3.1 μM). These results were supported by Aβ aggregation kinetics investigations and transmission electron microscopy studies, which demonstrate the suitability of DAQ ring system to develop antiamyloid agents as pharmacological tools to study Aβ aggregation. KEYWORDS: Quinazolines, amyloid, Aβ aggregation, Alzheimer's disease O ne of the most influential hallmarks of Alzheimer's pathology is the collapse of cellular amyloid management, leading to the progressive accumulation of neurotoxic Aβ-deposits. 1−4 While the mechanisms intertwining the amyloid pathway are vast and complex, a number of strategies to combat its neuronal insults have been proposed, researched, and evaluated in various preclinical and clinical settings. 5−7 An essential tool utilized by researchers to further understand the aggregation mechanisms of amyloidogenic peptides, such as Aβ, is to develop and evaluate aggregation modulators and inhibitors. 8,9 Not only is this beneficial in understanding the kinetics of amyloid aggregation but it may reveal potential therapeutic candidates.When it comes to developing drug candidates, nature plays an important role in highlighting ideas for potential core templates and scaffolds. Honing in on the case of Aβ with respect to aggregation modulators and inhibitors, compounds such as curcumin, a component of the spice turmeric, and resveratrol, a phytoalexin found in grapes and berries ( Figure 1), are considered as model compounds in this context. 10−13 The synthetic compound, orange G is a commonly used stain/ dye and, like curcumin and resveratrol, is used as a pharmacological tool in drug discovery due to its excellent activity against amyloid aggregation. 14,15From a chemical standpoint, these small molecules share structural features including aromaticity, conjugation, and planarity resulting in their ability to intercalate and disrupt the backbone hydrogen bonding interactions in the beta-sheet assembly thereby providing a framework to design small molecules as pharmacological tools to study Aβ aggregation and inhibition. 16,17 As part of our research program aimed at discovering and developing novel small-molecules as potential pharmacological tools to study Alzheimer's disease (AD) and

show abstract

The Amyloid Beta Peptide: A Chemist’s Perspective. Role in Alzheimer’s and Fibrillization

Cited by 783 publications

References 767 publications

A single-residue substitution inhibits fibrillization of Ala-based pentapeptides. A spectroscopic and molecular dynamics investigation

A single-residue substitution inhibits fibrillization of Ala-based pentapeptides. A spectroscopic and molecular dynamics investigation

Multifunctional Cholinesterase and Amyloid Beta Fibrillization Modulators. Synthesis and Biological Investigation

Structure–Activity Relationship Studies of Isomeric 2,4-Diaminoquinazolines on β-Amyloid Aggregation Kinetics

Contact Info

Product

Resources

About