Inhibition of protein aggregation and amyloid formation by small molecules

Doig, Andrew J.; Derreumaux, Philippe

doi:10.1016/j.sbi.2014.12.004

Cited by 274 publications

(225 citation statements)

References 48 publications

(50 reference statements)

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“…caution against its use due to favorable cross-interaction between wt and arginine substituted species that shift otherwise disordered I254R peptides into an aggregating state. Other approaches being investigated for targeting aggregates of p53 and other amyloids include use of modified peptides, molecular tweezers, and small molecule polyphenols, such as curcumin and resveratrol58. An important consideration for application of the aforementioned strategies for p53 is the unique nature of p53 aggregation.…”

Section: Discussionmentioning

confidence: 99%

Aggregation tendencies in the p53 family are modulated by backbone hydrogen bonds

Cino

Soares

Pedrote

et al. 2016

Sci Rep

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The p53 family of proteins is comprised of p53, p63 and p73. Because the p53 DNA binding domain (DBD) is naturally unstable and possesses an amyloidogenic sequence, it is prone to form amyloid fibrils, causing loss of functions. To develop p53 therapies, it is necessary to understand the molecular basis of p53 instability and aggregation. Light scattering, thioflavin T (ThT) and high hydrostatic pressure (HHP) assays showed that p53 DBD aggregates faster and to a greater extent than p63 and p73 DBDs, and was more susceptible to denaturation. The aggregation tendencies of p53, p63, and p73 DBDs were strongly correlated with their thermal stabilities. Molecular Dynamics (MD) simulations indicated specific regions of structural heterogeneity unique to p53, which may be promoted by elevated incidence of exposed backbone hydrogen bonds (BHBs). The results indicate regions of structural vulnerability in the p53 DBD, suggesting new targetable sites for modulating p53 stability and aggregation, a potential approach to cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Aggregation tendencies in the p53 family are modulated by backbone hydrogen bonds

Cino

Soares

Pedrote

et al. 2016

Sci Rep

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“…1 Interfering with Aβ production, its selfassembly and clearance is a potential treatment to prevent or delay the onset of the disease. 1,2 The Aβ40 peptide of sequence DAEFRHDSGYEVHHQKLVFFAEDVGSN KGAIIGLMVGGVV has a hydrophilic patch E22-G29 (loop region) separating two hydrophobic patches at L17-A21 (central hydrophobic core, CHC) and A30-V40 (C-terminus). The N-terminus spanning residues D1-K16 is also very hydrophilic with the residues D1, H6, H13 and H14 found to play a dominant role in metal ion interactions.…”

Section: Introductionmentioning

confidence: 99%

Structures of the Alzheimer’s Wild-Type Aβ1-40 Dimer from Atomistic Simulations

et al. 2015

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We have studied the dimer of amyloid beta peptide Aβ of 40 residues by means of all-atom replica exchange molecular dynamics. The Aβ-dimers have been found to be the smallest toxic species in Alzheimer's disease, but their inherent flexibilities have precluded structural characterization by experimental methods. Though the 24-μs-scale simulation reveals a mean secondary structure of 18% β-strand and 10% α helix, we find transient configurations with an unstructured N-terminus and multiple β-hairpins spanning residues 17-21 and 30-36, but the antiparallel and perpendicular peptide orientations are preferred over the parallel organization. Short-lived conformational states also consist of all α topologies, and one compact peptide with β-sheet structure stabilized by a rather extended peptide with α-helical content. Overall, this first all-atom study provides insights into the equilibrium structure of the Aβ1-40 dimer in aqueous solution, opening a new avenue for a comprehensive understanding of the impact of pathogenic and protective mutations in early-stage Alzheimer's disease on a molecular level.

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“…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.…”

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.

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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

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Inhibition of protein aggregation and amyloid formation by small molecules

Cited by 274 publications

References 48 publications

Aggregation tendencies in the p53 family are modulated by backbone hydrogen bonds

Aggregation tendencies in the p53 family are modulated by backbone hydrogen bonds

Structures of the Alzheimer’s Wild-Type Aβ1-40 Dimer from Atomistic Simulations

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

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