期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 58, 期 9, 页码 3875-3891出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b00139
关键词
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资金
- Natural Science Foundation of China [81273433, 91213302, 81330077]
- Research Fund for the Doctoral Program of Higher Education of China [20110171110051]
- Guangdong Provincial Key Laboratory of Construction Foundation [2011A060901014]
Up-regulation of a disintegrin and metalloptoteinase 10 (ADAM10) to prevent the formation of beta-amyloid (A beta) peptides might be a promising strategy to treat Alzheimer's disease (AD). RNA G-quadruplex motif within the 5'-UTR of the ADAM10 mRNA is an inhibitory element for ADAM10 translation. Thus, mitigation of the suppressive effect of this motif using an RNA G-quadruplex-forming G-rich sequence (QGRS) binder might be a new approach for AD therapy. Herein, a series of new methylquinolinium derivatives were synthesized and screened by surface plasmon resonance (SPR) and the dual-luciferase reporter assay. Among them, compound 24 showed selective affinity for the QGRS of ADAM10 and could strongly up-regulate the translation of it. Moreover, treatment with 24 led to a significant increase of the secretion of sAPP alpha, consequently decreasing the A beta(40) in cellular. These results illustrate that the ititeraction between the RNA QGRS and a small molecule may be a new molecular strategy to modulate the translation of ADAM10.
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