Tyrosine-Generated Nanostructures Initiate Amyloid Cross-Seeding in Proteins Leading to a Lethal Aggregation Trap

Anand, Bibin G.; Prajapati, Kailash Prasad; Shekhawat, Dolat Singh; Kar, Karunakar

doi:10.1021/acs.biochem.8b00472

Cited by 35 publications

(157 citation statements)

References 33 publications

(82 reference statements)

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“…But from our data, piperine might play a role in disintegrating the Aβ fibril formation. Recent studies reported that indirect involvement of piperine-coated gold formation was able to inhibit amyloid-prone residues of insulin (Anand et al, 2017, 2018). They found that the process of both spontaneous and seed-induced (misfolded protein aggregates) amyloid formation of insulin was strongly inhibited in the presence of piperine-coated gold nanoparticles.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Effects of Curcumin and Piperine as Potent Acetylcholine and Amyloidogenic Inhibitors With Significant Neuroprotective Activity in SH-SY5Y Cells via Computational Molecular Modeling and in vitro Assay

Manap

Tan

Leong

et al. 2019

Front. Aging Neurosci.

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Hallmarks of Alzheimer’s disease (AD) pathology include acetylcholine (ACh) deficiency and plaque deposition. Emerging studies suggest that acetylcholinesterase (AChE) may interact with amyloid β (Aβ) to promote aggregation of insoluble Aβ plaques in brains of patients. Current therapeutic options available for AD patients, such as AChE inhibitors, provide only symptomatic relief. In this study, we screened four natural compounds believed to harbor cognitive benefits—curcumin, piperine, bacoside A, and chebulinic acid. In the first section, preliminary screening through computational molecular docking simulations gauged the suitability of the compounds as novel AChE inhibitors. From here, only compounds that met the in silico selection criteria were selected for the second section through in vitro investigations, including AChE enzyme inhibition assay, 3-(4,5-dimenthylthiazol-2-yl)-2,5-dimethyltetrazolium bromide (MTT) assay, Thioflavin T (ThT) assay, and biochemical analysis via a neuronal cell line model. Of the four compounds screened, only curcumin (−9.6 kcal/mol) and piperine (−10.5 kcal/mol) showed favorable binding affinities and interactions towards AChE and were hence selected. In vitro AChE inhibition demonstrated that combination of curcumin and piperine showed greater AChE inhibition with an IC 50 of 62.81 ± 0.01 μg/ml as compared to individual compounds, i.e., IC 50 of curcumin at 134.5 ± 0.06 μg/ml and IC 50 of piperine at 76.6 ± 0.08 μg/ml. In the SH-SY5Y cell model, this combination preserved cell viability up to 85%, indicating that the compounds protect against Aβ-induced neuronal damage ( p < 0.01). Interestingly, our results also showed that curcumin and piperine achieved a synergistic effect at 35 μM with an synergism quotient (SQ) value of 1.824. Synergistic behavior indicates that the combination of these two compounds at lower concentrations may provide a better outcome than singularly used for Aβ proteins. Combined curcumin and piperine managed to inhibit aggregation (reduced ThT intensity at 0.432 a.u.; p < 0.01) as well as disaggregation (reduced ThT intensity at 0.532 a.u.; p < 0.01) of fibrillar Aβ42. Furthermore, combined curcumin and piperine reversed the Aβ-induced up-regulation of neuronal oxidative stress ( p < 0.01). In conclusion, curcumin and piperine demonstrated promising neuroprotective effects, whereas bacoside A and chebulinic acid may not be suitable lead compounds. These results are hoped to advance the field of natural products research as potentially therapeutic and curative AD agents.

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Section: Discussionmentioning

confidence: 99%

Synergistic Effects of Curcumin and Piperine as Potent Acetylcholine and Amyloidogenic Inhibitors With Significant Neuroprotective Activity in SH-SY5Y Cells via Computational Molecular Modeling and in vitro Assay

Manap

Tan

Leong

et al. 2019

Front. Aging Neurosci.

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“…1,2 Recently, our laboratory has revealed similar amyloid cross-seeding potential of tyrosine-generated nanostructures under mimicked physiological conditions of buffer and temperature. 4 Such research revelations on the ability of aromatic metabolites such as phenylalanine and tyrosine molecules to self-assemble into amyloid-like entities capable of initiating amyloid cross-seeding in proteins and other metabolites strongly validate the curiosity on the amyloidogenic nature of the aspartame molecule. We have sought answers to this critical question by exploring whether aspartame can spontaneously undergo an amyloid-like self-assembly process and probing what damaging effect such aggregation process would have on the proteins and cells.…”

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confidence: 94%

Self-Assembly of Artificial Sweetener Aspartame Yields Amyloid-like Cytotoxic Nanostructures

et al. 2019

Self Cite

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Recent reports have revealed the intrinsic propensity of single aromatic metabolites to undergo self-assembly and form nanostructures of amyloid nature. Hence, identifying whether aspartame, a universally consumed artificial sweetener, is inherently aggregation prone becomes an important area of investigation. Although the reports on aspartame-linked side effects describe a multitude of metabolic disorders, the mechanistic understanding of such destructive effects is largely mysterious. Since aromaticity, an aggregation-promoting factor, is intrinsic to aspartame’s chemistry, it is important to know whether aspartame can undergo self-association and if such a property can predispose any cytotoxicity to biological systems. Our study finds that aspartame molecules, under mimicked physiological conditions, undergo a spontaneous self-assembly process yielding regular β-sheet-like cytotoxic nanofibrils of amyloid nature. The resultant aspartame fibrils were found to trigger amyloid cross-seeding and become a toxic aggregation trap for globular proteins, Aβ peptides, and aromatic metabolites that convert native structures to β-sheet-like fibrils. Aspartame fibrils were also found to induce hemolysis, causing DNA damage resulting in both apoptosis and necrosis-mediated cell death. Specific spatial arrangement between aspartame molecules is predicted to form a regular amyloid-like architecture with a sticky exterior that is capable of promoting viable H-bonds, electrostatic interactions, and hydrophobic contacts with biomolecules, leading to the onset of protein aggregation and cell death. Results reveal that the aspartame molecule is inherently amyloidogenic, and the self-assembly of aspartame becomes a toxic trap for proteins and cells, exposing the bitter side of such a ubiquitously used artificial sweetener.

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“…The interactions between these aromatic residues are integral to the proper structure and function of proteins . Recently, the single amino acid tyrosine has been shown to self‐assemble into cross‐β‐like fibers through hydrogen bonding and π–π stacking, and the fibrils were shown to mediate the aggregation of proteins through amyloid cross‐seeding, illustrating the importance of tyrosine residues in controlling the structure and function of proteins . Additionally, the sheet‐forming propensities of all possible 7‐mer sequence domains occurring in the amyloidogenic protein β2m were studied, and an important role was ascribed to the tyrosine‐rich regions .…”

Section: The Role Of Tyrosine In Natural Systemsmentioning

confidence: 99%

Tyrosine‐Rich Peptides as a Platform for Assembly and Material Synthesis

et al. 2018

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The self‐assembly of biomolecules can provide a new approach for the design of functional systems with a diverse range of hierarchical nanoarchitectures and atomically defined structures. In this regard, peptides, particularly short peptides, are attractive building blocks because of their ease of establishing structure–property relationships, their productive synthesis, and the possibility of their hybridization with other motifs. Several assembling peptides, such as ionic‐complementary peptides, cyclic peptides, peptide amphiphiles, the Fmoc‐peptide, and aromatic dipeptides, are widely studied. Recently, studies on material synthesis and the application of tyrosine‐rich short peptide‐based systems have demonstrated that tyrosine units serve as not only excellent assembly motifs but also multifunctional templates. Tyrosine has a phenolic functional group that contributes to π–π interactions for conformation control and efficient charge transport by proton‐coupled electron‐transfer reactions in natural systems. Here, the critical roles of the tyrosine motif with respect to its electrochemical, chemical, and structural properties are discussed and recent discoveries and advances made in tyrosine‐rich short peptide systems from self‐assembled structures to peptide/inorganic hybrid materials are highlighted. A brief account of the opportunities in design optimization and the applications of tyrosine peptide‐based biomimetic materials is included.

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Tyrosine-Generated Nanostructures Initiate Amyloid Cross-Seeding in Proteins Leading to a Lethal Aggregation Trap

Cited by 35 publications

References 33 publications

Synergistic Effects of Curcumin and Piperine as Potent Acetylcholine and Amyloidogenic Inhibitors With Significant Neuroprotective Activity in SH-SY5Y Cells via Computational Molecular Modeling and in vitro Assay

Synergistic Effects of Curcumin and Piperine as Potent Acetylcholine and Amyloidogenic Inhibitors With Significant Neuroprotective Activity in SH-SY5Y Cells via Computational Molecular Modeling and in vitro Assay

Self-Assembly of Artificial Sweetener Aspartame Yields Amyloid-like Cytotoxic Nanostructures

Tyrosine‐Rich Peptides as a Platform for Assembly and Material Synthesis

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