Oligonucleotides conjugated with short chemically defined polyethylene glycol chains are efficient antisense agents.
Bottom Line: On the other hand, the attachment of long PEG chains negatively influences the pharmacodynamic effect by reducing the hybridization efficiency.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.
Affiliation: University of Vienna, Department of Pharmaceutical Chemistry, Althanstraße 14, 1090 Vienna, Austria.Show MeSH
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Mentions: To exclude any unspecific or toxic effects, cell proliferation rates were assessed after treatment with the modified oligonucleotides, applied without transfection enhancer (Fig. 3). In concentrations that resulted in successful gene silencing, none of the oligonucleotides reduced proliferation by more than 15%, with a 13% reduction caused by non-PEGylated phosphorothioate 7 (100 nM) being the most pronounced effect. Thus, PEGylation did not induce any negative effect on proliferation, indicating a good in vitro safety profile of the conjugates.
Affiliation: University of Vienna, Department of Pharmaceutical Chemistry, Althanstraße 14, 1090 Vienna, Austria.