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.