An <i>ortho</i>-Iminoquinone Compound Reacts with Lysine Inhibiting Aggregation while Remodeling Mature Amyloid Fibrils

Fernandes, Lucas; N, Moraes; Sagrillo, Fernanda S.; Magalhães, Augusto Vieira; Moraes, Marcela Cristina de; Romão, Luciana; Foguel, Débora; Grimster, Neil P.; Palhano, Fernando L.

doi:10.1021/acschemneuro.7b00017

Cited by 14 publications

(13 citation statements)

References 30 publications

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“…We opted to load the MPs with a small molecule called ortho-IQ that we previously characterized as an antiamyloidogenic compound. 28 The loading process was performed by incubating IQ with MP. Then, the sample was sonicated for 30 min to permeabilize the surface of the MPs, and in the end of 24 h incubation, the loaded MPs were centrifuged and washed to remove free IQ.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Therefore, our recent work has shown that IQ is an excellent option to inhibit amyloid α-syn aggregation and the remodeling of mature fibrils into amorphous species. 28 Herein, we produced EGCG MPs through an oxidative protocol described previously. 22 After a few modifications, we produced EGCG MPs that were characterized by several biophysical techniques.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Because of its ability to bind to primary amines, we reasoned that it might be possible to oxidize the lysine side chains of proteins under aqueous conditions. Therefore, our recent work has shown that IQ is an excellent option to inhibit amyloid α-syn aggregation and the remodeling of mature fibrils into amorphous species …”

Section: Introductionmentioning

confidence: 99%

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Green Tea Polyphenol Microparticles Based on the Oxidative Coupling of EGCG Inhibit Amyloid Aggregation/Cytotoxicity and Serve as a Platform for Drug Delivery

Fernandes

Messias

Pereira-Neves

et al. 2020

ACS Biomater. Sci. Eng.

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The accumulation of cross-β-sheet amyloid fibrils is a hallmark of all human amyloid diseases. The compound epigallocatechin-3-gallate (EGCG), the main polyphenol present in green tea, has been described to have beneficial effects in several pathologies, including amyloidogenic diseases. This polyphenol blocks amyloidogenesis and disaggregates a broad range of amyloidogenic peptides comprising amyloid fibrils in vitro. The mechanism by which EGCG acts in the context of amyloid aggregation is not clear. Most of the biological effects of EGCG are attributable to its antioxidant activity. However, EGCG-oxidized products appear to be sufficient for the majority of EGCG amyloid remodeling observed against some polypeptides. If controlled, EGCG oxidation can afford homogenous microparticles (MPs) and can serve as drug delivery agents. Herein, we produced EGCG MPs by oxidative coupling and analyzed their activity during the aggregation of the protein α-synuclein (α-syn), the main protein related to Parkinson’s disease. The MPs modestly remodeled mature amyloid fibrils and efficiently inhibited the amyloidogenic aggregation of α-syn. The MPs showed low cytotoxicity against both dopaminergic cells and microglial cells. The MPs reduced the cytotoxic effects of α-syn oligomers. Interestingly, the MPs were loaded with another antiamyloidogenic compound, increasing their activity against amyloid aggregation. We propose the use of EGCG MPs as a bifunctional strategy, blocking amyloid aggregation directly and carrying a molecule that can act synergistically to alleviate the symptoms caused by the amyloidogenic pathway.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Green Tea Polyphenol Microparticles Based on the Oxidative Coupling of EGCG Inhibit Amyloid Aggregation/Cytotoxicity and Serve as a Platform for Drug Delivery

Fernandes

Messias

Pereira-Neves

et al. 2020

ACS Biomater. Sci. Eng.

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“…These functional microparticles, with oxidized EGCG as carrier, have been shown to inhibit α-syn aggregation, reduce the cytotoxicity of oligomers and, modestly, remodel mature fibrils ( Fernandes et al, 2020 ). Moreover, when the EGCG microparticle was loaded with an additional amyloidogenesis inhibitor, ortho-iminoquinone ( Largeron and Fleury, 2012 ; Fernandes et al, 2017 ), its activity increased, demonstrating a synergistic action between the microcarrier and the loaded molecule ( Fernandes et al, 2020 ).…”

Section: Drug Delivery Systems Containin Epigallocatechin-gallatementioning

confidence: 99%

Green Tea Polyphenol Epigallocatechin-Gallate in Amyloid Aggregation and Neurodegenerative Diseases

et al. 2021

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The accumulation of protein aggregates in human tissues is a hallmark of more than 40 diseases called amyloidoses. In seven of these disorders, the aggregation is associated with neurodegenerative processes in the central nervous system such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). The aggregation occurs when certain soluble proteins lose their physiological function and become toxic amyloid species. The amyloid assembly consists of protein filament interactions, which can form fibrillar structures rich in β-sheets. Despite the frequent incidence of these diseases among the elderly, the available treatments are limited and at best palliative, and new therapeutic approaches are needed. Among the many natural compounds that have been evaluated for their ability to prevent or delay the amyloidogenic process is epigallocatechin-3-gallate (EGCG), an abundant and potent polyphenolic molecule present in green tea that has extensive biological activity. There is evidence for EGCG’s ability to inhibit the aggregation of α-synuclein, amyloid-β, and huntingtin proteins, respectively associated with PD, AD, and HD. It prevents fibrillogenesis (in vitro and in vivo), reduces amyloid cytotoxicity, and remodels fibrils to form non-toxic amorphous species that lack seed propagation. Although it is an antioxidant, EGCG in an oxidized state can promote fibrils’ remodeling through formation of Schiff bases and crosslinking the fibrils. Moreover, microparticles to drug delivery were synthesized from oxidized EGCG and loaded with a second anti-amyloidogenic molecule, obtaining a synergistic therapeutic effect. Here, we describe several pre-clinical and clinical studies involving EGCG and neurodegenerative diseases and their related mechanisms.

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“…Analyzing α-syn species by biochemical approaches, another small molecule, an ortho-iminoquinone (IQ) was shown to reduce amyloid aggregation by reacting with lysine residues. IQ also reacted with free amines within the amyloid fibrils preventing their dissociation and seeding capacity [232].…”

Section: Molecules Directly Interacting With α-Synmentioning

confidence: 99%

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

et al. 2020

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Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.

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An ortho-Iminoquinone Compound Reacts with Lysine Inhibiting Aggregation while Remodeling Mature Amyloid Fibrils

Cited by 14 publications

References 30 publications

Green Tea Polyphenol Microparticles Based on the Oxidative Coupling of EGCG Inhibit Amyloid Aggregation/Cytotoxicity and Serve as a Platform for Drug Delivery

Green Tea Polyphenol Microparticles Based on the Oxidative Coupling of EGCG Inhibit Amyloid Aggregation/Cytotoxicity and Serve as a Platform for Drug Delivery

Green Tea Polyphenol Epigallocatechin-Gallate in Amyloid Aggregation and Neurodegenerative Diseases

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

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