Design of peptide-based inhibitor agent against amyloid-β aggregation: Molecular docking, synthesis and in vitro evaluation

Jokar, Safura; Erfani, Mostafa; Bavi, Omid; Khazaei, Saeedeh; Sharifzadeh, Mohammad; Hajiramezanali, Malihe; Beiki, Davood; Shamloo, Amir

doi:10.1016/j.bioorg.2020.104050

Cited by 33 publications

(13 citation statements)

References 68 publications

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“…Many peptide-based candidates rationally designed to inhibit amyloid-beta aggregation have been derived from the sequence of amyloid-beta itself, exploiting its propensity for self-aggregation to facilitate targeted binding (Watanabe et al, 2002;Austen et al, 2008;Viet et al, 2011;Arai et al, 2014;Kino et al, 2015;Kumar et al, 2015;Cheng et al, 2017;Lu et al, 2019;Jokar et al, 2020). The majority of these peptides contain elements derived from amyloidogenic sequences involved in beta-sheet formation (Moss et al, 2003), such as the KLVFF (amyloid-beta 16-20 ) and GGVVIA (amyloid-beta 37-42 ) motifs, and are thus termed beta-sheet breakers (Soto et al, 1998).…”

Section: Cationic Arginine-rich Peptides As Aggregation Inhibitors For Alzheimer's Disease Inhibitory Peptides For Amyloid-beta Aggregatimentioning

confidence: 99%

Arginine and Arginine-Rich Peptides as Modulators of Protein Aggregation and Cytotoxicity Associated With Alzheimer’s Disease

Mamsa

Meloni

2021

Front. Mol. Neurosci.

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A substantial body of evidence indicates cationic, arginine-rich peptides (CARPs) are effective therapeutic compounds for a range of neurodegenerative pathologies, with beneficial effects including the reduction of excitotoxic cell death and mitochondrial dysfunction. CARPs, therefore, represent an emergent class of promising neurotherapeutics with multimodal mechanisms of action. Arginine itself is a known chaotrope, able to prevent misfolding and aggregation of proteins. The putative role of proteopathies in chronic neurodegenerative diseases such as Alzheimer’s disease (AD) warrants investigation into whether CARPs could also prevent the aggregation and cytotoxicity of amyloidogenic proteins, particularly amyloid-beta and tau. While monomeric arginine is well-established as an inhibitor of protein aggregation in solution, no studies have comprehensively discussed the anti-aggregatory properties of arginine and CARPs on proteins associated with neurodegenerative disease. Here, we review the structural, physicochemical, and self-associative properties of arginine and the guanidinium moiety, to explore the mechanisms underlying the modulation of protein aggregation by monomeric and multimeric arginine molecules. Arginine-rich peptide-based inhibitors of amyloid-beta and tau aggregation are discussed, as well as further modulatory roles which could reduce proteopathic cytotoxicity, in the context of therapeutic development for AD.

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Section: Cationic Arginine-rich Peptides As Aggregation Inhibitors For Alzheimer's Disease Inhibitory Peptides For Amyloid-beta Aggregatimentioning

confidence: 99%

Arginine and Arginine-Rich Peptides as Modulators of Protein Aggregation and Cytotoxicity Associated With Alzheimer’s Disease

Mamsa

Meloni

2021

Front. Mol. Neurosci.

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“…In comparison, in the presence of 10 and 40 B[a]P molecules, the helix region was prevalent (34% and 36%, respectively). Typically, the progression of Alzheimer's disease is associated with the formation of β-sheet fibrils [39,40], however, more simulation time will be required for the formation of the stable β-sheets from the random coils in the peptide oligomers [41]. Interestingly, the β-content did not significantly vary with different B[a]P concentrations, with 6-9% of the β-content observed in all systems under the study.…”

Section: Resultsmentioning

confidence: 91%

Ambient Benzo[a]pyrene’s Effect on Kinetic Modulation of Amyloid Beta Peptide Aggregation: A Tentative Association between Ultrafine Particulate Matter and Alzheimer’s Disease

Kaumbekova

Torkmahalleh

Shah

2022

Toxics

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Long-time exposure to ambient ultrafine particles is associated with an increased risk of neurodegenerative diseases such as Alzheimer’s disease (AD), which is triggered by the aggregation of Aβ peptide monomers into toxic oligomers. Among different ultrafine air pollutants, polycyclic aromatic hydrocarbons (PAHs) are known to have a negative neural impact; however, the impact mechanism remains obscure. We herein examined the effect of Benzo[a]Pyrene (B[a]P), one of the typical PAHs on Aβ42 oligomerization using all-atom molecular dynamics simulations. In particular, the simulations were performed using four molecules of Aβ42 in the presence of 5.00 mM, 12.5 mM, and 50.0 mM of B[a]P. The results revealed strong hydrophobic interactions between Aβ42 peptides and B[a]P, which in turn resulted in increased interpeptide electrostatic interactions. Furthermore, 5.00 mM of B[a]P accelerated the kinetics of the formation of peptide tetramer by 30%, and stabilized C-terminus in Aβ42 peptides, suggesting consequent progression of AD in the presence of 5.00 mM B[a]P. In contrast, 12.5 mM and 50.0 mM of B[a]P decreased interpeptide interactions and H-bonding due to the aggregation of numerous B[a]P clusters with the peptides, suppressing oligomerization kinetics of Aβ42 peptides by 13% and 167%, respectively. While the study elucidates the effect of small environmental hydrophobic molecules on the formation of Aβ oligomers, the impact of ambient ultrafine particles on AD in the complex composition of the environmental realm requires further systematic delving into the field.

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“…In the case of 1IYT, P12 interacts with Ala21, Lys28, Gly38, and Ala42 with H-bonding and also makes hydrophobic interaction with Ala42 and Lys28 (given in figure3a&3b). Joker et al stated that there are three structural properties of interaction that can destabilize the assembly of Amyloid-beta: 1) Electrostatic interaction between residues Asp23-Lys28 forms a hydrophilic region; 2) Glu22 helps in maintaining the stability between chains of fibrils and helps to remain intact, and 3) Residue in between Lys17-Ala21 & Ala30-Val42 from a hydrophobic region which can be the target region to mask and block oligomerization [45]. As shown in figure-4b, upon docking, peptide (P6) interacts with the backbone of Amyloid-beta fibril (2MXU) that lies within the binding pocket having the maximum D-score (as mentioned in table1).…”

Section: Molecular Docking Analysismentioning

confidence: 99%

In silico identification of novel peptides as potential modulators of Aβ42 Amyloidogenesis

Kundal

Paramasivam

Mitra

et al. 2022

Preprint

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Alzheimer’s Disease is a neurodegenerative disease for which no cure is available at present. The presence of amyloid plaques in the extracellular space of neural cells is the key feature of this fatal disease. Amyloid-Beta (Aβ) is a 40-42 amino acid peptide and the main component of amyloid plaques. This peptide is produced by the proteolysis of Amyloid Precursor Protein by presenilin. Deposition of 42 residual Aβ peptides forms fibrils structure, leading to disruption of neuron synaptic transmission, inducing neural cell toxicity, ultimately leading to neuron death. To modulate the amyloidosis of Aβ peptides, various novel peptides have been investigated via molecular docking and molecular dynamic simulation studies. The sequence-based peptides were designed and investigated for their interaction with Aβ42 monomer and fibril using the molecular docking method, and their influence on the structural stability of target proteins was studied using molecular simulations. According to the docking results, amongst all the synthetic peptides, the peptide YRIGY (P6) has the highest binding affinity with Aβ42 fibril, and the peptide DKAPFF (P12) shows better binding with Aβ42 monomer. Moreover, simulation results also suggest that the higher the binding affinity, the better the inhibitory action. From these findings, it is suggested that both the peptides can modulate the amyloidogenesis, but peptide (P6) has better potential for the disaggregation of the fibrils, whereas peptide P12 stabilizes the native structure of the Aβ42 monomer more effectively and hence can serve as a potential amyloid inhibitor. Thus, these peptides can be explored as therapeutic agents against Alzheimer’s Disease.

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Design of peptide-based inhibitor agent against amyloid-β aggregation: Molecular docking, synthesis and in vitro evaluation

Cited by 33 publications

References 68 publications

Arginine and Arginine-Rich Peptides as Modulators of Protein Aggregation and Cytotoxicity Associated With Alzheimer’s Disease

Arginine and Arginine-Rich Peptides as Modulators of Protein Aggregation and Cytotoxicity Associated With Alzheimer’s Disease

Ambient Benzo[a]pyrene’s Effect on Kinetic Modulation of Amyloid Beta Peptide Aggregation: A Tentative Association between Ultrafine Particulate Matter and Alzheimer’s Disease

In silico identification of novel peptides as potential modulators of Aβ42 Amyloidogenesis

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