title: Antisense and antigene inhibition of gene expression by cell-permeable oligonucleotide-oligospermine conjugates.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Gagnon
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Watts
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Pendergraff
authors.forename: Christophe
authors.initials: C
authors.lastname: Montaillier
authors.forename: Danielle
authors.initials: D
authors.lastname: Thai
authors.forename: Pierre
authors.initials: P
authors.lastname: Potier
authors.forename: David R
authors.initials: DR
authors.lastname: Corey
mesh_terms: D001483:Base Sequence; D002412:Cations; D002463:Cell Membrane Permeability / Q000187:drug effects; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D018014:Gene Transfer Techniques; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009841:Oligonucleotides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000037:antagonists & inhibitors*; D013096:Spermine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D002412:Cations; D004791:Enzyme Inhibitors; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D013096:Spermine