Antisense and Antigene Inhibition of Gene Expression by Cell-Permeable Oligonucleotide–Oligospermine Conjugates

Oligonucleotides and their derivatives are a proven chemical strategy for modulating gene expression. However, their negative charge remains a challenge for delivery and target recognition inside cells. Here we show that oligonucleotide–oligospermine conjugates (Zip nucleic acids or ZNAs) can help o...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2011-06, Vol.133 (22), p.8404-8407
Main Authors: Gagnon, Keith T, Watts, Jonathan K, Pendergraff, Hannah M, Montaillier, Christophe, Thai, Danielle, Potier, Pierre, Corey, David R
Format: Article
Language:English
Subjects:
Base Sequence
Cations
Cell Membrane Permeability - drug effects
Drug Delivery Systems
Enzyme Inhibitors - pharmacology
Gene Expression Regulation - drug effects
Gene Transfer Techniques
Inhibitory Concentration 50
Models, Biological
Models, Molecular
Molecular Sequence Data
Molecular Structure
Oligonucleotides - chemistry
Oligonucleotides - metabolism
Oligonucleotides - pharmacology
Oligonucleotides, Antisense - antagonists & inhibitors
Spermine - chemistry
Spermine - metabolism
Spermine - pharmacology
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Summary:Oligonucleotides and their derivatives are a proven chemical strategy for modulating gene expression. However, their negative charge remains a challenge for delivery and target recognition inside cells. Here we show that oligonucleotide–oligospermine conjugates (Zip nucleic acids or ZNAs) can help overcome these shortcomings by serving as effective antisense and antigene agents. Conjugates containing DNA and locked nucleic acid (LNA) oligonucleotides are active, and oligospermine conjugation facilitates carrier-free cell uptake at nanomolar concentrations. Conjugates targeting the CAG triplet repeat within huntingtin (HTT) mRNA selectively inhibit expression of the mutant huntingtin protein. Conjugates targeting the promoter of the progesterone receptor (PR) function as antigene agents to block PR expression. These observations support further investigation of ZNA conjugates as gene silencing agents.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja200312y