Big dynorphin is a neuroprotector scaffold against amyloid β-peptide aggregation and cell toxicity

Gallego-Villarejo, Lucía; Wallin, Cecilia; Król, Sylwia; Enrich-Bengoa, Jennifer; Suades, Albert; Aguilella‐Arzo, Marcel; Gómara, María J.; Haro, Isabel; Wärmländer, Sebastian K.T.S.; Muñoz, Francisco J.; Gräslund, Astrid; Perálvarez-Marín, Àlex

doi:10.1016/j.csbj.2022.10.014

Cited by 7 publications

(5 citation statements)

References 50 publications

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“…On the other hand, an almost equimolar Aβ40:alkaloid ratio was used to map peptide regions involved in the binding sites. For the NMR analysis, the Aβ40 isoform is usually preferred to Aβ42 [60,61], the latter being more prone to aggregate and thus is less appropriate for NMR measurements.…”

Section: Atomic and Molecular Interactions Between Gal/lyc And Aβmentioning

confidence: 99%

A Comparative Study between Lycorine and Galantamine Abilities to Interact with AMYLOID β and Reduce In Vitro Neurotoxicity

Kola

Lamponi

Currò

et al. 2023

IJMS

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Galantamine is a natural alkaloid extracted from the Amaryllidaceae plants and is used as the active ingredient of a drug approved for the treatment of the early stages of Alzheimer’s disease. It mainly acts as an acetylcholinesterase (AChE) inhibitor, increasing concentrations of the acetylcholine neurotransmitter. Recent cellular studies have also shown the ability of galantamine to protect SH-SY5Y cell lines against amyloid-β (Aβ)-induced toxicity. Such investigations have supported and validated further in-depth studies for understanding the chemical and molecular features associated with galantamine-protective abilities. In addition to galantamine, other natural alkaloids are known to possess AChE inhibitory activity; among them lycorine has been extensively investigated for its antibacterial, anti-inflammatory and antitumoral activities as well. Despite its interesting biological properties, lycorine’s neuroprotective functions against Aβ-induced damages have not been explored so far. In this research study, the ability of galantamine and lycorine to suppress Aβ-induced in vitro neuronal toxicity was evaluated by investigating the chemical interactions of the two alkaloids with Aβ peptide. A multi-technique spectroscopic analysis and cellular cytotoxicity assays were applied to obtain new insights on these molecular associations. The comparison between the behaviors exhibited by the two alkaloids indicates that both compounds possess analogue abilities to interact with the amyloidogenic peptide and protect cells.

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Section: Atomic and Molecular Interactions Between Gal/lyc And Aβmentioning

confidence: 99%

A Comparative Study between Lycorine and Galantamine Abilities to Interact with AMYLOID β and Reduce In Vitro Neurotoxicity

Kola

Lamponi

Currò

et al. 2023

IJMS

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“…DynA interacts with opioid receptors, namely κ-opioid receptor (KOR) and µ-opioid receptor (MOR), and plays a role in pain, stress, and addiction. Besides its opioid effects, DynA has other non-opioid activities, such as anti-amyloid properties [23] or interactions with N-methyl-D-aspartate (NMDA) receptors [24]. Furthermore, DynA is an amphipathic peptide, with a total positive net charge (+ 4), and adopts an α-helix structure when interacting with membranes [25], key characteristics of CPPs [10,26].…”

Section: Introductionmentioning

confidence: 99%

Unravelling the Cell-Penetrating Potential of Endogenous Opioid Neuropeptide Dynorphin A through Computational Dissection of Membrane Disruption Principles

Peralvarez-Marin,

Catalina-Hernandez,

Lopez-Martin

et al. 2024

Preprint

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Dynorphins are endogenous neuropeptides that function as opioids. In addition to opioid activity, dynorphins can induce several pathological effects such as neurological dysfunctions and cell death. Previous studies have suggested that Dynorphin A (DynA) and its clinical variants (L5S, R6W, and R9C) mediate some pathogenic actions through formation of transient pores in lipid domains of the plasma membrane. Here, we use a combination of steered and conventional molecular dynamics simulations to evaluate the ability of DynA and its variants to disturb lipid membranes in comparison to well established cell-penetrating peptides to determine how these peptides interact and permeate model lipid bilayers. We show that in our setup DynA and its variants (except for R9C) exhibit a strong membrane disturbing potential that may lead to translocation through the formation of water pores, which is likely prevented in cholesterol containing bilayers for R6W. When cholesterol and negative charge in the bilayers are present, the membrane disruption potential of DynA and its variants is minimal, but the hydrophobic-to-polar substitution in L5S favors peptide translocation. Altogether, these results show the importance of out-of-the-box computational studies to design membrane disruptive peptides to exploit their cell-penetrating and antimicrobial capabilities.

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“…The accumulation and aggregation of Aβ peptides can be influenced by a number of interacting factors 3,19 , such as other proteins and peptides 10,[20][21] , including other amyloidic peptides/proteins [22][23][24][25] , cationic molecules and metal ions [26][27][28] , and various small molecules 8 . Redox-active metal ions such as Cu(II) and Fe(II) are of special interest 27,29 , as they are present in the plaques of AD brains [30][31] .…”

Section: Introductionmentioning

confidence: 99%

Characterization of uranyl (UO₂²⁺) ion binding to amyloid beta (Aβ) peptides: effects on Aβ structure and aggregation

Berntsson

Vosough

Noormägi

et al. 2023

Preprint

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Uranium (U) is naturally present in ambient air, water, and soil, and depleted uranium (DU) is released into the environment via industrial and military activities. While the radiological damage from U is rather well understood, less is known about the chemical damage mechanisms, which dominate in DU. Heavy metal exposure is associated with numerous health conditions including Alzheimers disease (AD), the most prevalent age-related cause of dementia. The pathological hallmark of AD is deposition of amyloid plaques, consisting mainly of amyloid-β (Aβ) peptides aggregated into amyloid fibrils in the brain. However, the toxic species in AD are likely oligomeric Aβ aggregates. Exposure to heavy metals such as Cd, Hg, Mn, and Pb is known to increase Aβ production, and these metals bind to Aβ peptides and modulate their aggregation. Possible effects of U in AD pathology have been sparsely studied. Here, we use biophysical techniques to study in vitro interactions between Aβ peptides and uranyl ions, UO22+, of DU. We show for the first time that uranyl ions bind to Aβ peptides with affinities in the micromolar range, induce structural changes in Aβ monomers and oligomers, and inhibit Aβ fibrillization. General toxic mechanisms of uranyl ions could be modulation of protein folding, misfolding, and aggregation.

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Big dynorphin is a neuroprotector scaffold against amyloid β-peptide aggregation and cell toxicity

Cited by 7 publications

References 50 publications

A Comparative Study between Lycorine and Galantamine Abilities to Interact with AMYLOID β and Reduce In Vitro Neurotoxicity

A Comparative Study between Lycorine and Galantamine Abilities to Interact with AMYLOID β and Reduce In Vitro Neurotoxicity

Unravelling the Cell-Penetrating Potential of Endogenous Opioid Neuropeptide Dynorphin A through Computational Dissection of Membrane Disruption Principles

Characterization of uranyl (UO₂²⁺) ion binding to amyloid beta (Aβ) peptides: effects on Aβ structure and aggregation

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Big dynorphin is a neuroprotector scaffold against amyloid β-peptide aggregation and cell toxicity

Cited by 7 publications

References 50 publications

A Comparative Study between Lycorine and Galantamine Abilities to Interact with AMYLOID β and Reduce In Vitro Neurotoxicity

A Comparative Study between Lycorine and Galantamine Abilities to Interact with AMYLOID β and Reduce In Vitro Neurotoxicity

Unravelling the Cell-Penetrating Potential of Endogenous Opioid Neuropeptide Dynorphin A through Computational Dissection of Membrane Disruption Principles

Characterization of uranyl (UO22+) ion binding to amyloid beta (Aβ) peptides: effects on Aβ structure and aggregation

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Product

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Characterization of uranyl (UO₂²⁺) ion binding to amyloid beta (Aβ) peptides: effects on Aβ structure and aggregation