Discovery of Small Molecules for Up-Regulating the Translation of Antiamyloidogenic Secretase, a Disintegrin and Metalloproteinase 10 (ADAM10), by Binding to the G-Quadruplex-Forming Sequence in the 5′ Untranslated Region (UTR) of Its mRNA
Discovery of Small Molecules for Up-Regulating the Translation of Antiamyloidogenic Secretase, a Disintegrin and Metalloproteinase 10 (ADAM10), by Binding to the G-Quadruplex-Forming Sequence in the 5′ Untranslated Region (UTR) of Its mRNA
复制标题
发现通过结合 mRNA 5' 非翻译区 (UTR) 中的 G-四链体形成序列来上调抗淀粉样蛋白生成分泌酶（一种解整合素和金属蛋白酶 10 (ADAM10)）翻译的小分子
DOI：
10.1021/acs.jmedchem.5b00139
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发表时间：
2015-05-14
影响因子：
7.3
通讯作者：
Huang, Zhi-Shu
中科院分区：
文献类型：
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作者：
Dai, Jie;Liu, Zhen-Quan;Huang, Zhi-Shu
上调解整合素和金属蛋白酶 10 (ADAM10) 以防止 β-淀粉样 (Aβ) 肽的形成可能是治疗阿尔茨海默病 (AD) 的一种有前景的策略。 ADAM10 mRNA 5'-UTR 内的 RNA G 四链体基序是 ADAM10 翻译的抑制元件。因此，使用形成RNA G四联体的富含G序列（QGRS）结合物减轻该基序的抑制作用可能是AD治疗的一种新方法。在此，通过表面等离振子共振（SPR）和双荧光素酶报告基因测定合成并筛选了一系列新的甲基喹啉衍生物。其中，化合物24对ADAM10的QGRS表现出选择性亲和力，并能强烈上调其翻译。此外，用24处理导致sAPP α的分泌显着增加，从而减少细胞中的A beta(40)。这些结果说明RNA QGRS和小分子之间的迭代可能是调节ADAM10翻译的新分子策略。
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.