Cyclodextrins as Protective Agents of Protein Aggregation: An Overview

Oliveri, Valentina; Vecchio, Graziella

doi:10.1002/asia.201600259

Cited by 43 publications

(32 citation statements)

References 72 publications

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“…In particular, a number of anti‐aggregation compounds that prevent Aβ assembly or promote clearance of aggregates have been developed . Among Aβ aggregation inhibitors identified to date there are small organic molecules, including curcumin, 8‐hydroxyquinolines (HQs), but also sugars such as cyclodextrins (CyD) and trehalose have been shown to prevent protein unfolding and aggregation.…”

Section: Introductionmentioning

confidence: 99%

“…CyDs are cyclic oligosaccharides characterized by an external hydrophilic surface (the OH groups are disposed outside) and a hydrophobic cavity that can encapsulate hydrophobic molecules . Moreover, CyDs have shown a potential role as antiaggregant and neuroprotective agents in diseases, whose physiopathology is related to cholesterol homeostasis and amyloidosis …”

Section: Introductionmentioning

confidence: 99%

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Structural Isomers of Cyclodextrin‐Bearing IOX1 Compound as Inhibitors of Aβ Aggregation

2017

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Alzheimer′s disease represents a daunting challenge for healthcare because it affects millions of people worldwide. The abnormal assembly of amyloid‐beta peptides into amyloid aggregates is a pathological hallmark of Alzheimer's disease. Properly functionalized cyclodextrins modulate amyloidogenesis. Here, we report the synthesis and characterization of a 6‐monofunctionalized cyclodextrin‐bearing a quinoline derivative (IOX1). Moreover, we tested the ability of the new compound and its 3‐monofunctionalized isomer to inhibit self‐induced Aβ aggregation in order to understand if the two isomers differently modulate aggregation process. The results further establish the potential of cyclodextrin conjugates as modulators of Aβ aggregation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural Isomers of Cyclodextrin‐Bearing IOX1 Compound as Inhibitors of Aβ Aggregation

2017

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“…[5,6] Among these,p hthalocyanines are the most commonly investigated compounds, [7][8][9] whereas the effect of porphyrins on Ab aggregationa nd toxicity has been less explored. [12,13] We have recently reported that the conjugation of Tre [14,15] and CDs [16][17][18] with aromatic moieties could provide an ew strategy to prevent Ab aggregation. [12,13] We have recently reported that the conjugation of Tre [14,15] and CDs [16][17][18] with aromatic moieties could provide an ew strategy to prevent Ab aggregation.…”

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confidence: 99%

“…[10,11] Moreover,n umerous studies have also shown that sugars such as trehalose (Tre) and cyclodextrins (CDs)m ay be protectivea gainst neuronal degeneration observed in AD. [12,13] We have recently reported that the conjugation of Tre [14,15] and CDs [16][17][18] with aromatic moieties could provide an ew strategy to prevent Ab aggregation.…”

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confidence: 99%

Porphyrin Cyclodextrin Conjugates Modulate Amyloid Beta Peptide Aggregation and Cytotoxicity

Oliveri

Zimbone

Giuffrida

et al. 2018

Chemistry A European J

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Although fibrillara myloid beta peptide( A b)a ggregates are one of the major hallmarks of Alzheimer's disease, increasing evidences uggeststhat soluble Ab oligomers are the primaryt oxic species. Ta rgeting the oligomeric speciesc ould represent an effective strategy to interfere with Ab toxicity. In this work, the biological properties of 5[4-(6-O-b-cyclodextrin)-phenyl],10,15,20-tri(4-hydroxyphenyl)-porphyrina nd its zinc complex were tested, as new molecules that interactw ith Ab and effectively preventi ts cytotoxicity.W ef ound that these systems can cross the cell membrane to deliver Ab intracellularlya nd promote its clearance. Our resultsp rovide evidencef or the use of cyclodextrin-porphyrin derivatives as ap romising strategy to target amyloid aggregation.The amyloid beta peptide( A b)h as been implicated as am ajor component in the development of Alzheimer's disease (AD). Much efforth as therefore been made to investigate the compositiono fa myloid plaques, the mechanism underlying Ab fibril formation,a nd the parameters that could contribute to the Ab toxicity. Although fibrillar Ab aggregates are one of the major hallmarks of AD, increasing evidence suggestst hat soluble oligomers of the peptide are the primary toxic species. [1] The structure and formation of Ab oligomers have been largely investigated. However,t he interplay between conformation and size in determining their toxicityi sstill underd ebate.It has been reported that soluble Ab oligomers are organized into different structures ranging from dimers to dodecamers, Ab*56, [2] and Ab-derived diffusible ligands(ADDLs). [3] Therefore, targeting one of theset oxic oligomeric species could represent an effective strategy to interferew ith Ab toxicity. [4] Several small molecules, including tetrapyrrolic compounds, have been reported to modulate the amyloid aggregation of several proteins, such as tau, Ab,a nd a-synuclein. [5,6] Among these,p hthalocyanines are the most commonly investigated compounds, [7][8][9] whereas the effect of porphyrins on Ab aggregationa nd toxicity has been less explored. [10,11] Moreover,n umerous studies have also shown that sugars such as trehalose (Tre) and cyclodextrins (CDs)m ay be protectivea gainst neuronal degeneration observed in AD. [12,13] We have recently reported that the conjugation of Tre [14,15] and CDs [16][17][18] with aromatic moieties could provide an ew strategy to prevent Ab aggregation.Herein, we show that a bCD derivativeb earing ap orphyrin moiety 5[4-(6-O-b-cyclodextrin)-phenyl],10,15,20-tri(4-hydroxyphenyl)-porphyrin (CDTHPP,F igure 1A and Figure S1 in the Supporting Information) is effective in inhibiting Ab 42 cytotoxicity.C ontrarily, bCD is not effective, and THPP is toxic. We also report the synthesis of the Zn complex of CDTHPP (ZnCDTHPP), that was studiedt ot est the effect of the metali n modulating the biological properties of the conjugate CDTHPP. Moreover,w ei nvestigated in parallel the activity of bCD or 5,10,15,20-tetra(4-hydroxyphenyl)-porphyrin (THPP).First, we studied th...

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“…Studies on these conjugates indicated that CyD conjugation improves some features of the chelators and makes them multifunctional . CyDs have been studied as artificial chaperones and anti‐aggregant agents . Methyl‐β‐CyD has been reported to reduce α‐synuclein (αSyn) accumulation, a protein implicated in Parkinson's disease (PD) .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Study of Multifunctional Cyclodextrin–Deferasirox Hybrids

et al. 2019

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Metal dyshomeostasis is central to a number of disorders that result from, inter alia, oxidative stress, protein misfolding, and cholesterol dyshomeostasis. In this respect, metal deficiencies are usually readily corrected by treatment with supplements, whereas metal overload can be overcome by the use of metal‐selective chelation therapy. Deferasirox, 4‐[(3Z,5E)‐3,5‐bis(6‐oxo‐1‐cyclohexa‐2,4‐dienylidene)‐1,2,4‐triazolidin‐1‐yl]benzoic acid, Exjade, or ICL670, is used clinically to treat hemosiderosis (iron overload), which often results from multiple blood transfusions. Cyclodextrins are cyclic glucose units that are extensively used in the pharmaceutical industry as formulating agents as well as for encapsulating hydrophobic molecules such as in the treatment of Niemann–Pick type C or for hypervitaminosis. We conjugated deferasirox, via an amide coupling reaction, to both 6A‐amino‐6A‐deoxy‐β‐cyclodextrin and 3A‐amino‐3A‐deoxy‐2A(S),3A(S)‐β‐cyclodextrin, at the upper and lower rim, respectively, creating hybrid molecules with dual properties, capable of both metal chelation and cholesterol encapsulation. Our findings emphasize the importance of the conjugation of β‐cyclodextrin with deferasirox to significantly improve the biological properties and to decrease the cytotoxicity of this drug.

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Cyclodextrins as Protective Agents of Protein Aggregation: An Overview

Cited by 43 publications

References 72 publications

Structural Isomers of Cyclodextrin‐Bearing IOX1 Compound as Inhibitors of Aβ Aggregation

Structural Isomers of Cyclodextrin‐Bearing IOX1 Compound as Inhibitors of Aβ Aggregation

Porphyrin Cyclodextrin Conjugates Modulate Amyloid Beta Peptide Aggregation and Cytotoxicity

Synthesis and Study of Multifunctional Cyclodextrin–Deferasirox Hybrids

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