Efficient Synthesis of Light‐Triggered Circular Antisense Oligonucleotides Targeting Cellular Protein Expression. (17th April 2018)

• Record Type: Journal Article
• Authors: Yang, Linlin; Kim, Hyun Bum; Sul, Jai‐Yoon; Yeldell, Sean B.; Eberwine, James H.; Dmochowski, Ivan J.
• Is Part Of: Chembiochem. Volume 19:Number 12(2018)
• Page Start: 1250
• Page End: 1254
• Publication Date: 2018-04-17
• Subjects: antisense agents -- click chemistry -- light activation -- oligonucleotides -- photocaged compounds; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201800012
• Languages: English
• ISSNs: 1439-4227

Abstract

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. Abstract : It just clicks : Caged circular oligonucleotides allow photomodulation of gene expression in living cells. An efficient route for cyclizing an antisense oligodeoxynucleotide (AS‐ODN) incorporating a photocleavable linker (PL) is explored. Oligo cyclization is achieved for several sequences in nearly quantitative yields through intramolecular copper(I)‐catalyzed azide–alkyne cycloaddition.