title: Oligonucleotides conjugated with short chemically defined polyethylene glycol chains are efficient antisense agents.
abstract: Ligand conjugation is an attractive approach to rationally modify the poor pharmacokinetic behavior and cellular uptake properties of antisense oligonucleotides. Polyethylene glycol (PEG) attachment is a method to increase solubility of oligonucleotides and prevent the rapid elimination, thus increasing tissue distribution. On the other hand, the attachment of long PEG chains negatively influences the pharmacodynamic effect by reducing the hybridization efficiency. We examined the use of short PEG ligands on the in vitro effect of antisense agents. Circular dichroism showed that the tethering of PEG12-chains to phosphodiester and phosphorothioate oligonucleotides had no influence on their secondary structure and did not reduce the affinity to the counter strand. In an in vitro tumor model, a luciferase reporter assay indicated unchanged gene silencing activity compared to unmodified compounds, and even slightly superior target down regulation was found after treatment with a phosphorothioate modified conjugate.
authors.affiliation: University of Vienna, Department of Pharmaceutical Chemistry, Althanstraße 14, 1090 Vienna, Austria.
authors.forename: Nasrin
authors.initials: N
authors.lastname: Shokrzadeh
authors.affiliation: University of Vienna, Department of Pharmaceutical Chemistry, Althanstraße 14, 1090 Vienna, Austria.
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Winkler
authors.affiliation: University of Vienna, Department of Pharmaceutical Chemistry, Althanstraße 14, 1090 Vienna, Austria.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Dirin
authors.affiliation: University of Vienna, Department of Pharmaceutical Chemistry, Althanstraße 14, 1090 Vienna, Austria. Electronic address: johannes.winkler@univie.ac.at.
authors.forename: Johannes
authors.initials: J
authors.lastname: Winkler
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002942:Circular Dichroism; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D009841:Oligonucleotides / Q000737:chemistry*; D016376:Oligonucleotides, Antisense / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011092:Polyethylene Glycols / Q000737:chemistry*; D013873:Thionucleotides / Q000737:chemistry; D014162:Transfection
chemical_list: D008024:Ligands; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D011092:Polyethylene Glycols
keywords: Antisense agents; Bioconjugation; Oligonucleotides; Polyethylene glycol