Peptide‐Based Inhibitors of Amyloid Assembly

Sciarretta, Kimberly L.; Gordon, David; Meredith, Stephen C.

doi:10.1016/s0076-6879(06)13015-3

Cited by 129 publications

(140 citation statements)

References 97 publications

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“…The mitigators AAMP-20, AAMP-21, AAMP-24, and AAMP-25 were found to reduce Aβ 1-40 fluorescence by less than 40%, whereas AAMP-22 and AAMP-23 exhibited 80% reduced ThT fluorescence. On the basis of ThT results, only AAMP-11, AAMP-16, AAMP-22, and AAMP-23 exhibited a higher reduction in ThT fluorescence relative to Aβ than the N-methylated peptide, Aβ [16][17][18][19][20][21][22] m previously reported to disrupt fibril formation and to disassemble preformed fibrils (15).…”

Section: Effects Of Aamps On Aβ 1-40 Tht Fluorescencementioning

confidence: 87%

“…On the basis of ThT fluorescence only, various AAMPs tested exhibited reduced fluorescence comparable to that of the N-methylated control peptide. After 24 h, there is no significant difference in ThT fluorescence observed for AAMPs incorporating polar groups on the N-and C-termini (AAMP-11-15), C-terminus (AAMP- [16][17][18], N-terminus (AAMP-19), or RRAA-containing AAMPs (AAMP-20-25). It should also be noted that the reduced fluorescence exhibited by the various AAMPs do not necessarily indicate the absence of fibrils.…”

Section: Disassembly Of Preformed Fibrilsmentioning

confidence: 99%

“…Several groups have developed amyloid aggregation mitigating peptides (AAMPs) based on designed changes to the Αβ [16][17][18][19][20] central hydrophobic core, KLVFF fragment, which Tjenberg (11,12) showed to be critical for Aβ self-assembly and self-recognition. To the KLVFF core, a "disrupter" group is added that either solubilizes inhibitor-Aβ aggregates or blocks further addition of β-sheets through hydrogen bonding.…”

mentioning

confidence: 99%

“…Thus, mitigators containing bulky substituents (RRAAs) could be more effective at inducing β-sheet disassembly than peptides that incorporate proline. Simulation experiments have shown that N-methylated peptide Aβ16-22m interacts with the Aβ [16][17][18][19][20][21][22] blocking β-sheet extension, preventing lateral association into layers, and more importantly blocking inhibitor intercalation for sequestering Aβ peptides. However, Aβ16-22m has also been to shown in vivo to increase Aβ deposition in the brain of APP transgenic mice, unlike our peptide AMY-1 which showed ability to reduce Aβ deposits.…”

mentioning

confidence: 99%

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Effects of Peptides Derived from Terminal Modifications of the Aβ Central Hydrophobic Core on Aβ Fibrillization

Bett

Serem

Fontenot

et al. 2010

ACS Chem. Neurosci.

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Considerable research effort has focused on the discovery of mitigators that block the toxicity of the β-amyloid peptide (Aβ) by targeting a specific step involved in Aβ fibrillogenesis and subsequent aggregation. Given that aggregation intermediates are hypothesized to be responsible for Aβ toxicity, such compounds could likely prevent or mitigate aggregation, or alternatively cause further association of toxic oligomers into larger nontoxic aggregates. Herein we investigate the effect of modifications of the KLVFF hydrophobic core of Aβ by replacing N-and C-terminal groups with various polar moieties. Several of these terminal modifications were found to disrupt the formation of amyloid fibrils and in some cases induced the disassembly of preformed fibrils. Significantly, mitigators that incorporate MiniPEG polar groups were found to be effective against Aβ 1-40 fibrilligonesis. Previously, we have shown that mitigators incorporating alpha,alpha-disubstituted amino acids (RRAAs) were effective in disrupting fibril formation as well as inducing fibril disassembly. In this work, we further disclose that the number of polar residues (six) and RRAAs (three) in the original mitigator can be reduced without dramatically changing the ability to disrupt Aβ 1-40 fibrillization in vitro.

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Section: Effects Of Aamps On Aβ 1-40 Tht Fluorescencementioning

confidence: 87%

Section: Disassembly Of Preformed Fibrilsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Effects of Peptides Derived from Terminal Modifications of the Aβ Central Hydrophobic Core on Aβ Fibrillization

Bett

Serem

Fontenot

et al. 2010

ACS Chem. Neurosci.

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“…The major focus of drug design against AD is the inhibition of amyloid beta (Ab) peptide aggregation (Sciarretta et al 2006;Wang et al 2014), the causative pathogenic process as supported and established by the Amyloid cascade hypothesis (Hardy and Higgins 1992). According to this hypothesis, the proteolysis of an integral membrane protein-amyloid precursor protein (APP) causes the formation of amyloid beta peptides.…”

Section: Introductionmentioning

confidence: 99%

In silico study of peptide inhibitors against BACE 1

et al. 2015

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Peptides are increasingly used as inhibitors of various disease specific targets. Several naturally occurring and synthetically developed peptides are undergoing clinical trials. Our work explores the possibility of reusing the non-expressing DNA sequences to predict potential drugtarget specific peptides. Recently, we experimentally demonstrated the artificial synthesis of novel proteins from non-coding regions of Escherichia coli genome. In this study, a library of synthetic peptides (Synpeps) was constructed from 2500 intergenic E. coli sequences and screened against Beta-secretase 1 protein, a known drug target for Alzheimer's disease (AD). Secondary and tertiary protein structure predictions followed by proteinprotein docking studies were performed to identify the most promising enzyme inhibitors. Interacting residues and favorable binding poses of lead peptide inhibitors were studied. Though initial results are encouraging, experimental validation is required in future to develop efficient target specific inhibitors against AD.

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Interface Peptides

Peczuh¹,

Desmond²

2010

Protein Surface Recognition

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Peptide‐Based Inhibitors of Amyloid Assembly

Cited by 129 publications

References 97 publications

Effects of Peptides Derived from Terminal Modifications of the Aβ Central Hydrophobic Core on Aβ Fibrillization

Effects of Peptides Derived from Terminal Modifications of the Aβ Central Hydrophobic Core on Aβ Fibrillization

In silico study of peptide inhibitors against BACE 1

Interface Peptides

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