Rationally Designed Peptoids Modulate Aggregation of Amyloid-Beta 40

Turner, James; Lutz-Rechtin, Tammy; Moore, Kelly Ann; Rogers, L.S.; Bhave, Omkar; Moss, Melissa A.; Servoss, Shannon L.

doi:10.1021/cn400221u

Cited by 48 publications

(54 citation statements)

References 44 publications

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“…89 Mandal et al introduced ortho-aminobenzoic acid (Ant) in a known Ab inhibitor to obtain [Ac-L(Ant)FFD-NH 2 ] (4) as a modulator for both inhibition and dissolution of Ab40 aggregates. 89 Mandal et al introduced ortho-aminobenzoic acid (Ant) in a known Ab inhibitor to obtain [Ac-L(Ant)FFD-NH 2 ] (4) as a modulator for both inhibition and dissolution of Ab40 aggregates.…”

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confidence: 99%

Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

2015

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Amyloidogenesis has been implicated in a broad spectrum of diseases in which amyloid protein is invariably misfolded and deposited in cells and organs. Alzheimer's disease is one of the most devastating ailments among amyloidogenesis induced dementia. The amyloid beta (Aβ) peptide derived from amyloid precursor protein (APP) is misfolded and deposited as plaques in the brain, which are said to be the hallmark of Alzheimer's disease. In normal brains physiological concentration of the Aβ peptide has been indicated to be involved in modulating neurogenesis and synaptic plasticity. However, excess Aβ production, its aggregation and deposition deleteriously affect a large number of biologically important pathways leading to neuronal cell death. Targeting Aβ production, Aβ aggregation or its clearance from the brain has been an active area of research for preventing or curing AD. Our Feature Article intends to detail the aggregation mechanism, the physiological role of the Aβ peptide, elaborate its toxic effects, and outline the different classes of molecules designed in the last two years to inhibit amyloidogenic APP processing, Aβ oligomerization or fibrillogenesis and to modulate different pathways for active clearance of Aβ from the brain.

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Section: View Article Onlinementioning

confidence: 99%

Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

2015

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“…Numerous variations on this approach have been published, where the sequence is modified or appending domains are attached to improve its efficacy. 20–24 In a second approach, peptide libraries are screened for binding to full-length A β . 25–28 The library-screening approach requires little or no a priori knowledge of desired sequence or structural features.…”

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confidence: 99%

TANGO-Inspired Design of Anti-Amyloid Cyclic Peptides

Lū

Brickson

Murphy

2016

ACS Chem. Neurosci.

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β-Amyloid peptide (Aβ) self-associates into oligomers and fibrils, in a process that is believed to directly lead to neuronal death in Alzheimer’s disease. Compounds that bind to Aβ, and inhibit fibrillogenesis and neurotoxicity, are of interest as an anti-Alzheimer therapeutic strategy. Peptides are particularly attractive for this purpose, because they have advantages over small molecules in their ability to disrupt protein–protein interactions, yet they are amenable to tuning of their properties through chemical means, unlike antibodies. Self-complementation and peptide library screening are two strategies that have been employed in the search for peptides that bind to Aβ. We have taken a different approach, by designing Aβ-binding peptides using transthyretin (TTR) as a template. Previously, we demonstrated that a cyclic peptide, with sequence derived from the known Aβ-binding site on TTR, suppressed Aβ aggregation into fibrils and protected neurons against Aβ toxicity. Here, we searched for cyclic peptides with improved efficacy, by employing the algorithm TANGO, designed originally to identify amyloidogenic sequences in proteins. By using TANGO as a guide to predict the effect of sequence modifications on conformation and aggregation, we synthesized a significantly improved cyclic peptide. We demonstrate that the peptide, in binding to Aβ, redirects Aβ toward protease-sensitive, nonfibrillar aggregates. Cyclic peptides designed using this strategy have attractive solubility, specificity, and stability characteristics.

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“…Aβ oligomeric species were prepared through standard protocols and were detected using immunohistochemistry (IHC) in dot blot analysis. 40 Figure S3). The data revealed that GHK did not prevent the formation of oligomeric species, whereas LPFFD and SrVSrFSr showed ~60% and ~75% inhibition, respectively.…”

Section: Inhibition Of Aβ Oligomeric Aggregatesmentioning

confidence: 99%

Natural Tripeptide-Based Inhibitor of Multifaceted Amyloid β Toxicity

Rajasekhar

Madhu

Govindaraju

2016

ACS Chem. Neurosci.

119

137

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Accumulation of amyloid beta (Aβ) peptide and its aggregates in the human brain is considered as one of the hallmarks of Alzheimer's disease (AD). The polymorphic oligomers and fully grown fibrillar aggregates of Aβ exhibit different levels of neuronal toxicity. Moreover, aggregation of Aβ in the presence of redox-active metal ions like Cu(2+) is responsible for the additional trait of cellular toxicity induced by the generation of reactive oxygen species (ROS). Herein, a multifunctional peptidomimetic inhibitor (P6) has been presented, based on a naturally occurring metal chelating tripeptide (GHK) and the inhibitor of Aβ aggregation. It was shown by employing various biophysical studies that P6 interact with Aβ and prevent the formation of toxic Aβ forms like oligomeric species and fibrillar aggregates. Further, P6 successfully sequestered Cu(2+) from the Aβ-Cu(2+) complex and maintained it in a redox-dormant state to prevent the generation of ROS. P6 inhibited membrane disruption by Aβ oligomers and efficiently prevented DNA damage caused by the Aβ-Cu(2+) complex. PC12 cells were rescued from multifaceted Aβ toxicity when treated with P6, and the amount of ROS generated in cells was reduced. These attributes make P6 a potential therapeutic candidate to ameliorate the multifaceted Aβ toxicity in AD.

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Rationally Designed Peptoids Modulate Aggregation of Amyloid-Beta 40

Cited by 48 publications

References 44 publications

Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

Function and toxicity of amyloid beta and recent therapeutic interventions targeting amyloid beta in Alzheimer's disease

TANGO-Inspired Design of Anti-Amyloid Cyclic Peptides

Natural Tripeptide-Based Inhibitor of Multifaceted Amyloid β Toxicity

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