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Efficient Synthesis of Light-Triggered Circular Antisense Oligonucleotides Targeting Cellular Protein Expression
Linlin Yang1, Hyun Bum Kim2, Jai-Yoon Sul2
1Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA, 19104-6323, USA.
Chembiochem : a European Journal of Chemical Biology
|February 27, 2018
Summary
We developed a new method to create stable, light-activated antisense oligonucleotides. These cyclized caged oligos efficiently reduce gene expression, like GFAP, in cells upon photoactivation.
Area of Science:
- Molecular Biology
- Biochemistry
- Oligonucleotide Chemistry
Background:
- Light-activated ("caged") antisense oligonucleotides offer precise control over gene expression.
- Cyclized caged oligos exhibit enhanced stability, mimicking natural circular nucleic acids.
Purpose of the Study:
- To establish an efficient method for cyclizing antisense oligodeoxynucleotides with photocleavable linkers.
- To characterize the stability and light-activation properties of the cyclized caged oligos.
- To demonstrate the gene-silencing efficacy of a cyclized caged oligo targeting GFAP.
Main Methods:
- Intramolecular copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) for oligo cyclization.
- Förster resonance energy transfer (FRET) efficiency, denaturing gel electrophoresis, and melting temperature analysis for characterization.
- Application of a cyclized caged oligo targeting glial fibrillary acidic protein (GFAP) in astrocytes.
Main Results:
- Nearly quantitative yields achieved for oligo cyclization across multiple sequences.
- Demonstrated stability of caging and effective light-induced activation.
- A tenfold reduction in glial fibrillary acidic protein (GFAP) expression observed in astrocytes post-photoactivation.
Conclusions:
- Developed an efficient CuAAC-based cyclization strategy for antisense oligonucleotides.
- Validated the stability and photo-responsive gene-silencing capabilities of cyclized caged oligos.
- Showcased the potential of targeted gene regulation in astrocytes using these novel molecules.
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