title: 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.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Dai
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
authors.forename: Zhen-Quan
authors.initials: ZQ
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
authors.forename: Xiao-Qin
authors.initials: XQ
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lin
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
authors.forename: Pei-Fen
authors.initials: PF
authors.lastname: Yao
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
authors.forename: Shi-Liang
authors.initials: SL
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
authors.forename: Tian-Miao
authors.initials: TM
authors.lastname: Ou
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
authors.forename: Jia-Heng
authors.initials: JH
authors.lastname: Tan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
authors.forename: Lian-Quan
authors.initials: LQ
authors.lastname: Gu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
authors.forename: Zhi-Shu
authors.initials: ZS
authors.lastname: Huang
mesh_terms: D020121:5' Untranslated Regions; D051722:ADAM Proteins / Q000096:biosynthesis* / Q000235:genetics; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis* / Q000235:genetics; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054856:G-Quadruplexes; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D014176:Protein Biosynthesis; D011806:Quinolinium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C000599954:2-(2-(9-ethyl-9H-carbazol-3-yl)vinyl)-1-methyl-4-(4-methylpiperazin-1-yl)quinolin-1-ium; D020121:5' Untranslated Regions; D002227:Carbazoles; D008565:Membrane Proteins; D011806:Quinolinium Compounds; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human