Crown ethers attenuate aggregation of amyloid beta of Alzheimer's disease

Tian, Yanli; Zhang, Xueli; Li, Yuyan; Shoup, Timothy M.; Teng, Xin; Elmaleh, David R.; Moore, Anna; Ran, Chongzhao

doi:10.1039/c4cc06029f

Cited by 28 publications

(38 citation statements)

References 35 publications

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“…Given the amyloid-like properties of small metabolite assemblies and the ability of known amyloid inhibitors to inhibit the formation of phenylalanine [32][33][34]40 and tyrosine 33,41 assemblies, it is of great interest to examine whether chemical agents known to inhibit the assembly of protein and peptide-based amyloid structures can also restrict the formation of these metabolite fibrils. Furthermore, owing to the similarity between the protein and metabolite assemblies, the later can serve as an attractive minimalistic model to probe the mechanism of amyloid inhibition, which is yet to be fully deciphered.…”

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confidence: 99%

Differential inhibition of metabolite amyloid formation by generic fibrillation-modifying polyphenols

et al. 2018

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The formation of ordered amyloid fibrils by proteins and polypeptides is associated with human disorders. A recent extension of the amyloidogenic building block family includes several small metabolites, which form assemblies with structural and functional similarities to well-established amyloids. Here we investigate whether generic amyloid polyphenolic inhibitors can also restrict the formation of metabolite fibrils. We reveal that epigallocatechin gallate and tannic acid inhibit amyloid-like fibrillation of adenine, phenylalanine, and tyrosine. Moreover, the compounds reduce the cytotoxicity triggered by these assemblies. In contrast, acetylsalicylic acid, used as a control does not have an inhibitory effect. The compounds' differential effects at various time points is consistent with molecular dynamics simulations, providing information about the inhibition mechanisms and inhibitors' key interactions with the monomeric and subsequent crystalline fibril states. Taken together, we provide additional evidence for the fundamental similarities between protein-and metabolite-based amyloids, the inhibition process and dynamics of association.

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confidence: 99%

Differential inhibition of metabolite amyloid formation by generic fibrillation-modifying polyphenols

et al. 2018

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“…Previously we found that 12-crown-4 could attenuate the aggregation of Aβs. 13 Reportedly, crown ethers could form hydrogen bonds with positively charged amino groups (e.g. lysine, arginine, histidine) to shield the charge, 14 and the sequence of Aβ peptides contains important lysine (K16), a crucial amino acid that forms inter-sheet salt bridges and 6 promotes mis-folding of Aβ.…”

Section: Resultsmentioning

confidence: 99%

“…9 Previously, we found that 12-crown-4 showed decreased level of Aβ aggregates, confirmed by fluorescence assay and TEM observation. 13 To further prove that the charge editing effect could break the salt bridge of Aβ and change protein aggregation behaviors, SDS-page gel studies were performed. As expected, the addition of 12-crown-4, 18-crown-6 and Orange G significantly changed aggregation behaviors of Aβs, as indicated by reduced aggregation of low molecular weight of Aβs ( Supplementary Fig.10).…”

Section: Resultsmentioning

confidence: 99%

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A screening platform based on epitope editing for drug discovery

Zhu

Yang

Van

et al. 2019

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The interaction between an antibody and its epitope has been daily utilized in various biological studies; however it has been rarely explored whether small molecules can alter the interaction. We discovered that small molecules could alter/edit surface properties of amyloid beta (Aβ) epitopes, and consequently inhibit or enhance corresponding antibody recognition. Remarkably, this editing effect could generate functional changes including protein aggregation behaviors, cell cytokine secreting and in vivo microglia activation. According to this discovery, we proposed a screen 2 platform based on epitope editing for drug discovery (SPEED). With a small library of compounds, we validated that SPEED could be used to seek new leads for Aβ species.We also demonstrated that this platform could potentially be extended to other targets including tau protein and PD-L1 protein. The SPEED is a simple, fast and label-free screening method. We believe that the SPEED strategy could be universally applicable for seeking and validating drug candidates and imaging ligands.

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“…Thus, the molecules with abilities to inhibit or reduce the level of toxic oligomer and pathological fibril of Aβ may be used as drugs for AD treatment. Previously, positive results from the testing this strategy had been received by treatment with small ether compounds such as cycloalkyl ether, noladin ether, and 12-crown 4 cyclic polyether [16][17][18][19]. Particularly, the latter with a cyclic structure showed in silico and in vitro anti-Aβ aggregation, and it reduced its toxicity in Aβ42treated SH-SY5Y cells [18,19].…”

Section: Introductionmentioning

confidence: 99%

Beneficial Effects of Cyclic Ether 2-Butoxytetrahydrofuran from Sea Cucumber Holothuria scabra against Aβ Aggregate Toxicity in Transgenic Caenorhabditis elegans and Potential Chemical Interaction

et al. 2021

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The pathological finding of amyloid-β (Aβ) aggregates is thought to be a leading cause of untreated Alzheimer’s disease (AD). In this study, we isolated 2-butoxytetrahydrofuran (2-BTHF), a small cyclic ether, from Holothuria scabra and demonstrated its therapeutic potential against AD through the attenuation of Aβ aggregation in a transgenic Caenorhabditis elegans model. Our results revealed that amongst the five H. scabra isolated compounds, 2-BTHF was shown to be the most effective in suppressing worm paralysis caused by Aβ toxicity and in expressing strong neuroprotection in CL4176 and CL2355 strains, respectively. An immunoblot analysis showed that CL4176 and CL2006 treated with 2-BTHF showed no effect on the level of Aβ monomers but significantly reduced the toxic oligomeric form and the amount of 1,4-bis(3-carboxy-hydroxy-phenylethenyl)-benzene (X-34)-positive fibril deposits. This concurrently occurred with a reduction of reactive oxygen species (ROS) in the treated CL4176 worms. Mechanistically, heat shock factor 1 (HSF-1) (at residues histidine 63 (HIS63) and glutamine 72 (GLN72)) was shown to be 2-BTHF’s potential target that might contribute to an increased expression of autophagy-related genes required for the breakdown of the Aβ aggregate, thus attenuating its toxicity. In conclusion, 2-BTHF from H. scabra could protect C. elegans from Aβ toxicity by suppressing its aggregation via an HSF-1-regulated autophagic pathway and has been implicated as a potential drug for AD.

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Crown ethers attenuate aggregation of amyloid beta of Alzheimer's disease

Cited by 28 publications

References 35 publications

Differential inhibition of metabolite amyloid formation by generic fibrillation-modifying polyphenols

Differential inhibition of metabolite amyloid formation by generic fibrillation-modifying polyphenols

A screening platform based on epitope editing for drug discovery

Beneficial Effects of Cyclic Ether 2-Butoxytetrahydrofuran from Sea Cucumber Holothuria scabra against Aβ Aggregate Toxicity in Transgenic Caenorhabditis elegans and Potential Chemical Interaction

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