Han X et al. (2017), A resorcinarene for inhibition of Aβ fibrillation.

ECB-ART-45449

Chem Sci 2017 Mar 01;83:2003-2009. doi: 10.1039/c6sc04854d.

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A resorcinarene for inhibition of Aβ fibrillation.

Han X , Park J , Wu W , Malagon A , Wang L , Vargas E , Wikramanayake A , Houk KN , Leblanc RM .

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Amyloid-β peptides (Aβ) fibrillation is the hallmark of Alzheimer''s disease (AD). However, it has been challenging to discover potent agents in order to inhibit Aβ fibrillation. Herein, we demonstrated the effect of resorcinarene on inhibiting Aβ fibrillation in vitro via experimental and computational methods. Aβ were incubated with different concentrations of resorcinarene so as to monitor the kinetics by using thioflavin T binding assay. The results, which were further confirmed by far-UV CD spectroscopy and atomic force microscopy, strongly indicated that the higher concentration of resorcinarene, the more effective the inhibition of Aβ fibrillation. A cytotoxicity study showed that when sea urchin embryos were exposed to the resorcinarene, the majority survived due to the resorcinarene low toxicity. In addition, when the resorcinarene was added, the formation of toxic Aβ 42 species was delayed. Computational studies of Aβ fibrillation, including docking simulations and MD simulations, illustrated that the interaction between inhibitor resorcinarene and Aβ is driven by the non-polar interactions. These studies display a novel strategy for the exploration of promising antiamyloiddogenic agents for AD treatments.

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Genes referenced: LOC100887844

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	Fig. 1. A schematic overview in vitro study of Aβ fibrillation, which includes the conformational transition from monomer to partially folded intermediate or oligomer to mature fibrils.
	Scheme 1. The structure of resorcinarene.
	Fig. 2. (a) Kinetics of 10 μM of Aβ 42 and Aβ 40 fibrillation: fluorescence intensity of thioflavin T (ThT) at 485 nm as a function of incubation time at 37 °C in 25 mM PBS, pH 7.4 with the ratio of Aβ to 1 at 1 : 0, 1 : 0.1, 1 : 1, and 1 : 5, respectively. The final concentration was a 2-fold dilution with 20 μM ThT. Baseline was corrected against the spectra of 1 (Fig. S2†). The ThT fluorescence was obtained for three repeats of each sample. The error bars indicate the standard error of the mean. (b) Far-UV circular dichroism spectra of 10 μM Aβ 42 alone (top panel) in 25 mM pH = 7.4 PBS at 0, 12, 48, 72 h, and 10 μM Aβ 42 incubated with 10 μM 1 (bottom panel), in 25 mM pH = 7.4 PBS at 0, 24, 48, 96 h. AFM images (size: 2.5 × 2.5 μm) of 10 μM Aβ 42 incubated at 37 °C in 25 mM PBS, pH 7.4 with (c) 0 μM, (d) 1 μM, and (e) 10 μM 1, respectively.
	Fig. 3. (a) Cytotoxicity test of resorcinarene to seaurchin embryos. (b) The inhibitory effect of resorcinarene on the cytotoxicity of Aβ 42 fibrils at different molar ratios of Aβ 42 to resorcinarene.
	Fig. 4. Predicted interactions of the resorcinearene and the Aβ 42 amyloid filament. Two of the relatively stable interactions patterns are predicted using the PELE and the MD simulations: (a) and (b). The last snapshots from the MD simulations are illustrated. Root-mean-squared deviations from the initial docked structure (blue), the last configuration of the MD simulation (red), and the buried surface area of the ligand–protein interface (orange) of each are plotted on bottom.

References [+] :

Arosio, Quantification of the concentration of Aβ42 propagons during the lag phase by an amyloid chain reaction assay. 2014, Pubmed