Efficient Synthesis of Light-Triggered Circular Antisense Oligonucleotides Targeting Cellular Protein Expression

Chembiochem : a European Journal of Chemical Biology
Linlin YangIvan J Dmochowski

Abstract

Light-activated ("caged") antisense oligonucleotides are powerful molecules for regulating gene expression at submicron spatial resolution through the focal modulation of endogenous cellular processes. Cyclized caged oligos are particularly promising structures because of their inherent stability and similarity to naturally occurring circular DNA and RNA molecules. Here, we introduce an efficient route for cyclizing an antisense oligodeoxynucleotide incorporating a photocleavable linker. Oligo cyclization was achieved for several sequences in nearly quantitative yields through intramolecular copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). Caging stability and light activation were characterized by FRET efficiency, denaturing gel assay, and melting temperature measurements. Finally, a cyclized caged oligo was designed to target gfap, and it gave a tenfold reduction in glial fibrillary acidic protein upon photoactivation in astrocytes.

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Citations

Jul 14, 2020·Biochemical Society Transactions·Denis HartmannMichael J Booth
Dec 13, 2019·Chemical Communications : Chem Comm·Yasuaki KimuraHiroshi Abe
Oct 31, 2020·Chembiochem : a European Journal of Chemical Biology·Zhe SuiXingguo Liang
Dec 22, 2020·Chemical Communications : Chem Comm·Robin KlimekAlexander Heckel
Jan 25, 2021·Advanced Drug Delivery Reviews·Teresa L Rapp, Cole A DeForest
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Linlin Yang, Ivan J Dmochowski
May 14, 2021·Trends in Biotechnology·Jiahui Zhang, Khalid Salaita
Aug 14, 2020·Bioconjugate Chemistry·Linlin YangIvan J Dmochowski
Sep 18, 2021·Organic & Biomolecular Chemistry·Jun-Ichi Mihara, Kenzo Fujimoto
Nov 6, 2021·Chemical Society Reviews·Kristie E Darrah, Alexander Deiters

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