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

作者：Dai, Jie; Liu, Zhen-Quan; Wang, Xiao-Qin; Lin, Jing; Yao, Pei-Fen; Huang, Shi-Liang; Ou, Tian-Miao; Tan, Jia-Heng; Li, Ding; Gu, Lian-Quan; Huang, Zhi-Shu^*

来源：Journal of Medicinal Chemistry, 2015, 58(9): 3875-3891.

DOI：10.1021/acs.jmedchem.5b00139

• AMYLOID PRECURSOR PROTEIN
• STABLE G-QUADRUPLEX
• ALPHA-SECRETASE
• ALZHEIMERS-DISEASE
• INHIBITION
• 5'-UTR
• EXPRESSION
• CLEAVAGE
• DEFECTS
• REPEATS

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.

• 出版日期2015-5-14
• 单位中山大学