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.

Abstract	Up-regulation of a disintegrin and metalloproteinase 10 (ADAM10) to prevent the formation of β-amyloid (Aβ) 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 sAPPα, consequently decreasing the Aβ40 in cellular. These results illustrate that the interaction between the RNA QGRS and a small molecule may be a new molecular strategy to modulate the translation of ADAM10.
Authors	Jie Dai, Zhen-Quan Liu, Xiao-Qin Wang, Jing Lin, Pei-Fen Yao, Shi-Liang Huang, Tian-Miao Ou, Jia-Heng Tan, Ding Li, Lian-Quan Gu, Zhi-Shu Huang
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 9 Pg. 3875-91 (May 14 2015) ISSN: 1520-4804 [Electronic] United States
PMID	25822852 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	2-(2-(9-ethyl-9H-carbazol-3-yl)vinyl)-1-methyl-4-(4-methylpiperazin-1-yl)quinolin-1-ium 5' Untranslated Regions Carbazoles Membrane Proteins Quinolinium Compounds RNA, Messenger Amyloid Precursor Protein Secretases ADAM Proteins ADAM10 Protein ADAM10 protein, human
Topics	5' Untranslated Regions ADAM Proteins (biosynthesis, genetics) ADAM10 Protein Amyloid Precursor Protein Secretases (biosynthesis, genetics) Carbazoles (chemical synthesis, chemistry, pharmacology) G-Quadruplexes HEK293 Cells HeLa Cells Humans Membrane Proteins (biosynthesis, genetics) Protein Biosynthesis Quinolinium Compounds (chemical synthesis, chemistry, pharmacology) RNA, Messenger (genetics, metabolism) Stereoisomerism Structure-Activity Relationship

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