Oligonucleotides conjugated with short chemically defined polyethylene glycol chains are efficient antisense agents.
Bottom Line: 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.
Affiliation: University of Vienna, Department of Pharmaceutical Chemistry, Althanstraße 14, 1090 Vienna, Austria.Show MeSH
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Mentions: Breast cancer cells MCF-7 were treated with both phosphodiesters (1 and 3) and phosphorothioates (4 and 5) with and without 3′-PEG ligand (Fig. 2). After co-transfection with lipofectamine 2000, all tested oligonucleotides resulted in significant gene silencing (Fig. 2A, p < 0.05). Neither statistically significant enhancement nor decrease of the effect was detected by the PEGylation of the phosphodiester backbone compound. In contrast, the PEGylated phosphorothioate 5 showed higher gene silencing activity than its non-PEGylated counterpart 4 after transfection in a concentration of 100 nM (p < 0.05).
Affiliation: University of Vienna, Department of Pharmaceutical Chemistry, Althanstraße 14, 1090 Vienna, Austria.