A resorcinarene for inhibition of Aβ fibrillation

Han, Xu; Park, Jiyong; Wu, Wei; Malagón, Andrés; Wang, Lingyu; Vargas, Édgar F.; Wikramanayake, Athula H.; Houk, K. N.; Leblanc, Roger M.

doi:10.1039/c6sc04854d

Cited by 45 publications

(30 citation statements)

References 48 publications

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“…Although aggregation of amyloid proteins has been studied extensively, there are only a few studies on disaggregation of the amyloids (18)(19)(20). For example, a large number of small molecules are known to inhibit amyloid aggregation (42)(43)(44), but very few molecules have been found to cause disaggregation of amyloids (45,46). A major difficulty in studying disaggregation is that amyloids are known to be extremely stable, sometimes practically insoluble even under strongly denaturing conditions.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Characterization of Metastability and Heterogeneity of Amyloid Aggregates

Sil

Sahoo

Bera

et al. 2018

Biophysical Journal

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Amyloids are heterogeneous assemblies of extremely stable fibrillar aggregates of proteins. Although biological activities of the amyloids are dependent on its conformation, quantitative evaluation of heterogeneity of amyloids has been difficult. Here we use disaggregation of the amyloids of tetramethylrhodamine-labeled Aβ (TMR-Aβ) to characterize its stability and heterogeneity. Disaggregation of TMR-Aβ amyloids, monitored by fluorescence recovery of TMR, was negligible in native buffer even at low nanomolar concentrations but the kinetics increased exponentially with addition of denaturants such as urea or GdnCl. However, dissolution of TMR-Aβ amyloids is different from what is expected in the case of thermodynamic solubility. For example, the fraction of soluble amyloids is found to be independent of total concentration of the peptide at all concentrations of the denaturants. Additionally, soluble fraction is dependent on growth conditions such as temperature, pH, and aging of the amyloids. Furthermore, amyloids undissolved in a certain concentration of the denaturant do not show any further dissolution after dilution in the same solvent; instead, these require higher concentrations of the denaturant. Taken together, our results indicate that amyloids are a heterogeneous ensemble of metastable states. Furthermore, dissolution of each structurally homogeneous member requires a unique threshold concentration of denaturant. Fraction of soluble amyloids as a function of concentration of denaturants is found to be sigmoidal. The sigmoidal curve becomes progressively steeper with progressive seeding of the amyloids, although the midpoint remains unchanged. Therefore, heterogeneity of the amyloids is a major determinant of the steepness of the sigmoidal curve. The sigmoidal curve can be fit assuming a normal distribution for the population of the amyloids of various kinetic stabilities. We propose that the mean and the standard deviation of the normal distribution provide quantitative estimates of mean kinetic stability and heterogeneity, respectively, of the amyloids in a certain preparation.

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Section: Discussionmentioning

confidence: 99%

Quantitative Characterization of Metastability and Heterogeneity of Amyloid Aggregates

Sil

Sahoo

Bera

et al. 2018

Biophysical Journal

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“…When the balance between the production and clearance of Aβ fibrils is upset, it undergoes conformation transition from random coil to an α-helix intermediate and finally to β-sheet rich structure accompanied by the gradual accumulation process from monomeric Aβ, soluble oligomeric intermediates to insoluble amyloid the synaptic plasticity, deregulation of Ca homeostasis and result in 5 6 the gradual synaptic loss, neuronal death, and cognitive decline. On this basis, exploring efficient methods to regulate the self-aggregation [7][8][9][10][11][12][13][14][15] process of Aβ has aroused great attention in diverse areas. Until now, plenty of researches have focused on developing effective fibril inhibitors and β-sheet breakers to disturb the aggregation 11,16 of Aβ or dissociate the preformed Aβ fibrils.…”

Section: Introductionmentioning

confidence: 99%

Attenuation of the Aggregation and Neurotoxicity of Amyloid Peptides with Neurotransmitter-Functionalized Ultra-Small-Sized Gold Nanoparticles

Xu¹,

Li²,

Lin³

et al. 2019

Eng. Sci.

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Alzheimer's disease (AD) is closely associated with the self-aggregation of beta-amyloid peptides (Aβ). The neuron cytotoxicity of assembled Aβ fibrils has been extensively studied. In this work, ultra-small-sized gold nanoparticles (USGNPs, with diameter of ~4 nm) are synthesized and conjugated with neurotransmitter dopamine (DA) and its synthetic precursors (L-phenylalanine (L-Phe) and L-tyrosine (L-Tyr)). It is found that the fibrillation process of Aβ can be efficiently inhibited by these functionalized USGNPs, which is essentially ascribed to the screened growth points on the short seeds after being anchored by functionalized USGNPs as well as the disturbing of the peptide folding process in solution as revealed by the transmission electron microscope (TEM) and circular dichroism (CD) spectroscopic measurements. More interestingly, the neuron cells (PC12 as a model) exhibit noticeably improved viability (~90%) when treated with functionalized USGNPs in contrast to the control treated with Aβ growth solution alone (~70%). Because of the superior inhibition effect on the Aβ fibrillation as well as the remarkable cell protection effect, these functionalized USGNPs would afford insight information for the rational design of efficient strategy for AD treatment.

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“…We have varied the ration of reagents as well as reaction conditions, and we chose those for which the nanocarrier is stable at normal glucose level but it dissociates at high glucose concentration. The sulfonated resorcinarene used in the nanocarrier synthesis is non‐toxic, its synthesis consists of two simple steps with inexpensive reagents . In this article, we report on the synthesis and properties of a glucose‐sensitive nanocarrier and its application in insulin delivery.…”

Section: Introductionmentioning

confidence: 99%

A Glucose‐Responsive Polymer Nanocarrier Based on Sulfonated Resorcinarene for Controlled Insulin Delivery

et al. 2019

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A nanocarrier (p(6SRA‐5B)) for glucose‐controlled insulin delivery consists of sulfonated resorcinarenes (SRA) that are assembled into a spherical shell and are attached to each other with phenylboronate linkers. p(6SRA‐5B) is stable in water and blood plasma at normal glucose concentrations. At high glucose levels (>5 mM), p(6SRA‐5B) dissociates into SRA and phenylboronates through competitive interaction with excess glucose. Insulin was successfully encapsulated into the cavity of p(6SRA‐5B) and its release was investigated in water and blood plasma by NMR, UV, CD, and fluorescence spectroscopy. The results show that the dissociation of the nanocarrier and the insulin release occurs with an increase in glucose concentration. At 5 mM glucose, the nanocarrier is stable, and the insulin release does not exceed 10 %. Increasing the glucose concentration to 7.5–10 mM results in a 40–100 % insulin release. p(6SRA‐5B) is thus a promising insulin nanocarrier for the treatment of type 1 diabetes.

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A resorcinarene for inhibition of Aβ fibrillation

Abstract: Low toxic resorcinarene can effectively inhibit Aβ fibrillation and delay the formation of toxic Aβ 42 species.

Cited by 45 publications

References 48 publications

Quantitative Characterization of Metastability and Heterogeneity of Amyloid Aggregates

Quantitative Characterization of Metastability and Heterogeneity of Amyloid Aggregates

Attenuation of the Aggregation and Neurotoxicity of Amyloid Peptides with Neurotransmitter-Functionalized Ultra-Small-Sized Gold Nanoparticles

A Glucose‐Responsive Polymer Nanocarrier Based on Sulfonated Resorcinarene for Controlled Insulin Delivery

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