Supramolecular Inhibition of Amyloid Fibrillation by Cucurbit[7]uril

Lee, Hong Hee; Choi, Tae Su; Lee, Shin Jung C.; Lee, Jong Wha; Park, Junghong; Ko, Young Ho; Kim, Won Jong; Kim, Kimoon; Kim, Hugh I.

doi:10.1002/anie.201402496

Cited by 131 publications

(113 citation statements)

References 28 publications

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“…S2)—a well-defined model system for amyloid fibrillation 25, 32 — exists as a monomer in formic acid (FA) using solution small-angle X-ray scattering (SAXS). The radius of gyration ( R g ) of INS (0.76 mg/mL in 1% FA) is 10.8 Å from the Guinier analysis of the scattering profile of INS (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Nanoscale Control of Amyloid Self-Assembly Using Protein Phase Transfer by Host-Guest Chemistry

Choi

Lee

et al. 2017

Sci Rep

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Amyloid fibrils have recently been highlighted for their diverse applications as functional nanomaterials in modern chemistry. However, tight control to obtain a targeted fibril length with low heterogeneity has not been achieved because of the complicated nature of amyloid fibrillation. Herein, we demonstrate that fibril assemblies can be homogeneously manipulated with desired lengths from ~40 nm to ~10 μm by a phase transfer of amyloid proteins based on host-guest chemistry. We suggest that host-guest interactions with cucurbit[6]uril induce a phase transfer of amyloid proteins (human insulin, human islet amyloid polypeptide, hen egg lysozyme, and amyloid-β 1–40 & 1–42) from the soluble state to insoluble state when the amount of cucurbit[6]uril exceeds its solubility limit in solution. The phase transfer of the proteins kinetically delays the nucleation of amyloid proteins, while the nuclei formed in the early stage are homogeneously assembled to fibrils. Consequently, supramolecular assemblies of amyloid proteins with heterogeneous kinetics can be controlled by protein phase transfer based on host-guest interactions.

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Section: Resultsmentioning

confidence: 99%

Nanoscale Control of Amyloid Self-Assembly Using Protein Phase Transfer by Host-Guest Chemistry

Choi

Lee

et al. 2017

Sci Rep

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“…9,10,12,13 As a result of the high affinity and high selectivity displayed by CB[ n ] compounds toward their guests, they have been used in a variety of applications including stimuli-responsive molecular machines, sensing ensembles, biomimetic processes, supramolecular polymers, (targeted) drug delivery, and drug reversal. 14 Given the high K a values typically observed for CB[ n ]•guest complexes, we realized that CB[ n ]-type receptors represent a potential alternative to the γ-cyclodextrin derivative Sugammadex ( 1 ) for the reversal of neuromuscular block. Among the known CB[ n ], only CB[8] and CB[10] are large enough to encapsulate the steroidal nucleus of NMBAs like rocuronium, but unfortunately the water solubility of these containers is poor (<100 μm) which severely limits their potential to function as in vivo reversal agents for NMBAs.…”

Section: Introductionmentioning

confidence: 99%

In Vitro selectivity of an acyclic cucurbit[n]uril molecular container towards neuromuscular blocking agents relative to commonly used drugs

et al. 2016

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An acyclic cucurbit[n]uril (CB[n]) based molecular container (2, a.k.a. Calabadion 2) binds to both amino-steroidal and benzylisoquinolinium type neuromuscular blocking agents (NMBAs) in vitro, and reverses the effect of these drugs in vivo displaying faster recovery times than placebo and the γ-cyclodextrin (CD) based and clinically used reversal agent Sugammadex. In this study we have assessed the potential for other drugs commonly used during and after surgery (e.g. antibiotics, antihistamines, and antiarrhythmics) to interfere with the ability of 2 to bind NMBAs rocuronium and cisatracurium in vitro. We measured the binding affinities (Ka, M−1) of twenty seven commonly used drugs towards 2 and simulated the equilibrium between 2, NMBA, and drug based on their standard clinical dosages to calculate the equilibrium concentration of 2•NMBA in the presence of the various drugs. We found that none of the 27 drugs studied possess the combination of a high enough binding affinity with 2 and a high enough standard dosage to be able to promote the competitive dissociation (a.k.a. displacement interactions) of the 2•NMBA complex with the formation of the 2•drug complex. Finally, we used the simulations to explore how the potential for displacement interactions is affected by a number of factors including the Ka of the 2•NMBA complex, the Ka of the AChR•NMBA complex, the Ka of the 2•drug complex, and the dosage of the drug.

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“…[14,17] Ab 1-x containst hree phenylalanine residues (Phe-4,P he-19, Phe-20), yet the weak interaction between CB [7] and middle chain Phe (K a $ 1 Â 10 4 M À1 )m ade it requirem ore CB [7] (about 100 times) to inhibit the aggregation of Ab. [18] In contrast, the aggregation of insulin was successfully inhibited by CB [7] at ar atio of 1:0.5 (insulin:CB [7]). [18] These resultssuggested the importance of the ion-dipole interactions between CB [7] and the amino group of N-terminal Phe.…”

Section: Introductionmentioning

confidence: 99%

Differential Modulation of the Aggregation of N‐Terminal Truncated Aβ using Cucurbiturils

Gao

Yang

Zhao

et al. 2018

Chemistry A European J

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Modulating the aggregation of Aβ has long been considered to be one of the potential methods to treat Alzheimer's disease (AD). It has been found that different Aβ species, including N-terminal truncated or/and modified Aβ, co-exist in the brain of AD patients. Yet, there is currently little detailed work about the specific modulation of these Aβ species which hinders us to understand their roles in patients' brain. Using thioflavin T (ThT) kinetics and transmission electron microscope, here we showed that cucurbit[7]uril and cucurbit[8]uril could inhibit the aggregation of both Aβ and Aβ through host-guest interactions. Chemical kinetics analysis suggested that this happened through inhibiting the elongation process by binding with fibril ends. In addition, cucurbiturils showed greater capability on the inhibition of Aβ than Aβ , which was possibly due to the N-terminal phenylalanine residue of Aβ . Our work provided new insights for the development of host-guest chemistry based inhibitors for the aggregation of different Aβ species.

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Supramolecular Inhibition of Amyloid Fibrillation by Cucurbit[7]uril

Cited by 131 publications

References 28 publications

Nanoscale Control of Amyloid Self-Assembly Using Protein Phase Transfer by Host-Guest Chemistry

Nanoscale Control of Amyloid Self-Assembly Using Protein Phase Transfer by Host-Guest Chemistry

In Vitro selectivity of an acyclic cucurbit[n]uril molecular container towards neuromuscular blocking agents relative to commonly used drugs

Differential Modulation of the Aggregation of N‐Terminal Truncated Aβ using Cucurbiturils

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