New mimetic peptides inhibitors of Αβ aggregation. Molecular guidance for rational drug design

Guisasola, Exequiel Ernesto Barrera; Andújar, Sebastián Antonio; Hubin, Ellen; Broersen, Kerensa; Kraan, Ivonne M.; Méndez, Luciana; Delpiccolo, Carina M. L.; Masman, Marcelo F.; Rodrı́guez, Ana; Enriz, Ricardo D.

doi:10.1016/j.ejmech.2015.03.042

Cited by 19 publications

(17 citation statements)

References 69 publications

(71 reference statements)

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“…[6] Extracellular amyloid plaques are dense, insoluble aggregates containing the Aβ peptide, which in the brain are produced primarily by neurons. [7] Aβ is a short peptide, with the most common alloforms being either 40 or 42 residues in length, [8] and is formed via proteolysis of the amyloid precursor protein (APP) by βand γ-secretases. [9,10] While Aβ 40 is the more abundant amyloid peptide in vivo, Aβ 42 is more neurotoxic and is responsible for peptide aggregation and fibrilization.…”

Section: Introductionmentioning

confidence: 99%

Rationally designed peptide-based inhibitor of Aβ42 fibril formation and toxicity: a potential therapeutic strategy for Alzheimer's disease

Horsley

Jovcevski

Wegener

et al. 2020

Biochemical Journal

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Amyloid beta peptide (Aβ42) aggregation in the brain is thought to be responsible for the onset of Alzheimer's disease, an insidious condition without an effective treatment or cure. Hence, a strategy to prevent aggregation and subsequent toxicity is crucial. Bio-inspired peptide-based molecules are ideal candidates for the inhibition of Aβ42 aggregation, and are currently deemed to be a promising option for drug design. In this study, a hexapeptide containing a self-recognition component unique to Aβ42 was designed to mimic the β-strand hydrophobic core region of the Aβ peptide. The peptide is comprised exclusively of D-amino acids to enhance specificity towards Aβ42, in conjunction with a C-terminal disruption element to block the recruitment of Aβ42 monomers on to fibrils. The peptide was rationally designed to exploit the synergy between the recognition and disruption components, and incorporates features such as hydrophobicity, β-sheet propensity, and charge, that all play a critical role in the aggregation process. Fluorescence assays, native ion-mobility mass spectrometry (IM-MS) and cell viability assays were used to demonstrate that the peptide interacts with Aβ42 monomers and oligomers with high specificity, leading to almost complete inhibition of fibril formation, with essentially no cytotoxic effects. These data define the peptide-based inhibitor as a potentially potent anti-amyloid drug candidate for this hitherto incurable disease.

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Section: Introductionmentioning

confidence: 99%

Rationally designed peptide-based inhibitor of Aβ42 fibril formation and toxicity: a potential therapeutic strategy for Alzheimer's disease

Horsley

Jovcevski

Wegener

et al. 2020

Biochemical Journal

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“…Compound 47a and 47b showed best inhibitory activity both in MD/docking studies and in biophysical assays. 158 Compound 47b affected the monomer structure of Aβ42 preserving its helical content and prevented the formation of the "toxic turn" involved in the propagation of toxic oligomers.…”

Section: Acs Combinatorial Sciencementioning

confidence: 98%

“…In 2015, Enriz et al reported a series of peptide mimetics 47 with the general structure as shown in Figure as potential inhibitors of Aβ aggregation. Compound 47a and 47b showed best inhibitory activity both in MD/docking studies and in biophysical assays . Compound 47b affected the monomer structure of Aβ42 preserving its helical content and prevented the formation of the “toxic turn” involved in the propagation of toxic oligomers.…”

Section: Peptide Inhibitors Of Amyloid-β (Aβ) Aggregationmentioning

confidence: 98%

Rationally Designed Peptides and Peptidomimetics as Inhibitors of Amyloid-β (Aβ) Aggregation: Potential Therapeutics of Alzheimer’s Disease

2017

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Alzheimer's disease (AD) is a progressive neurodegenerative disease with no clinically accepted treatment to cure or halt its progression. The worldwide effort to develop peptide-based inhibitors of amyloid-β (Aβ) aggregation can be considered an unplanned combinatorial experiment. An understanding of what has been done and achieved may advance our understanding of AD pathology and the discovery of effective therapeutic agents. We review here the history of such peptide-based inhibitors, including those based on the Aβ sequence and those not derived from that sequence, containing both natural and unnatural amino acid building blocks. Peptide-based aggregation inhibitors hold significant promise for future AD therapy owing to their high selectivity, effectiveness, low toxicity, good tolerance, low accumulation in tissues, high chemical and biological diversity, possibility of rational design, and highly developed methods for analyzing their mode of action, proteolytic stability (modified peptides), and blood-brain barrier (BBB) permeability.

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“…According to that, the peptide did not adopt any strict secondary structure and in a dynamic ensemble the random coil dominates, which complemented with low propensity of other secondary structure elements. Small molecules as well as peptide mimetics can modify the secondary structure profile of the peptide [30][31][32], thus it is reasonable to assume that covalently bonded molecular dyes can affect the conformational ensemble of the monomer.…”

Section: Secondary Structure Elementsmentioning

confidence: 99%

Fluorescence-Labeled Amyloid Beta Monomer: A Molecular Dynamical Study

Gera

Paragi

2020

Molecules

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The aggregation process of the Amyloidβ (Aβ) peptide is one of the central questions in Alzheimers’s research. Fluorescence-labeled single-molecule detection is a novel technique concerning the early stage investigation of Aβ aggregation, where the labeling dyes are covalently bound to the Aβ monomer. As the influence of the dye on the conformational space of the Aβ monomer can be significant, its effect on the seeding process is an open question. The applied fluorescent molecule continuously switches between an active (ON) and an inactive (OFF) state, where the latter supports an extra rotational restriction at many commercially available dyes. However, only a few theoretical studies simulated the Aβ monomer in the presence of a dye and none of them considered the difference between the ON and the OFF states. Therefore, we examined the impact of a selected fluorescence dye (Alexa 568) on the conformational space of the monomeric Aβ(1–42) peptide in its ON and OFF state by replica exchange molecular dynamic simulations. Investigations on secondary structure elements as well as dye-peptide contact analysis for the monomers are presented. Experimental and theoretical NMR shifts were contrasted to qualify the calculation protocol and theoretical values of the labeled and the non-labeled peptide were also compared. We found that the first five residues have higher helical propensity in the presence of the dye, and electrostatic properties could strongly affect the connection between the dye and the peptide parts.

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New mimetic peptides inhibitors of Αβ aggregation. Molecular guidance for rational drug design

Cited by 19 publications

References 69 publications

Rationally designed peptide-based inhibitor of Aβ42 fibril formation and toxicity: a potential therapeutic strategy for Alzheimer's disease

Rationally designed peptide-based inhibitor of Aβ42 fibril formation and toxicity: a potential therapeutic strategy for Alzheimer's disease

Rationally Designed Peptides and Peptidomimetics as Inhibitors of Amyloid-β (Aβ) Aggregation: Potential Therapeutics of Alzheimer’s Disease

Fluorescence-Labeled Amyloid Beta Monomer: A Molecular Dynamical Study

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