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ChemComm
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DOI: 10.1039/C7CC05056A
COMMUNICATION
ChemComm
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Molecular docking studies were carried out to gain more
details on the reasonable interactions of MC-1 and Aβ fibrils.
As shown in Fig. S18, the probe MC-1 inserts into the grooves
on the KLVFFA fibril surface, which was a hydrophobic binding
pocket paralleling to the main fibril axis formed by Val 18 and
Phe 20. Besides from the predominant hydrophobic
interaction and
π-π stacking interaction between the probe
and the nonpolar residues Val 18 and Phe 20, two hydrogen
bonds between the hydrogen atoms of a polar residue Lys 16
and the nitrogen atom of the cyano-group was observed. Thus,
the enhancement of fluorescence intensity of the probe might
be resulted from its inserting into the hydrophobic pocket,
which leads to a restrained double-bond isomerization or
rotational relaxation. Overall, the computational studies were
consistent with the experimental studies.
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To conclude, two merocyanine-based NIR fluorescence
probes were rationally designed and developed based on the
classical cyanine scaffold IR-780, in which MC-1 showed
significant turn-on fluorescence upon binding with Aβ
aggregates and good selectivity towards Aβ aggregates over
other proteins. Also, the in vivo imaging and ex vivo staining
studies proved that MC-1 can penetrate the BBB efficiently
and discriminate APP/PS1 transgenic mice from WT controls by
the specific binding of Aβ plaques. All these excellent
properties of this probe make it a robust and promising
imaging tool for the basic research for Alzheimer’s disease, and
even potential clinical application. This is the first example of
the development of neutral fluorescent probes derived from
cationic cyanine dyes for neurodegenerative disease, which
would shed light on the further exploiting of cyanine dyes.
Further optimization of these probes is in progress in our lab.
This work was financially supported by the National Natural
Science Foundation of China (21502056), the Natural Science
Foundation of Guangdong Province, China (2016A030310463)
and the Fundamental Research Funds for the Central
Universities (2017MS079) to Jin-wu Yan.
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4 | Chem. Commun., 2017, 00, 1-4
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