Abstract
Chemically modified oligodeoxynucleotides (ODNs) are known to modulate gene expression by interacting with RNA. An efficient approach for synthesizing amino acid- or peptide-substituted triazolylphosphonate analogs (TP ODNs) has been developed to provide improved stability and cell uptake. The chemistry is quite general, as peptides can be introduced throughout the TP ODN at any preselected internucleotide linkage. These synthetic TP ODNs enter cells through endocytosis in the absence of transfection reagents and localize into perinuclear organelles. The entrapped ODNs are released into the cytoplasm by treatment with endosomal-releasing agents and several are then active as microRNA inhibitors.
Highlights
Oligodeoxynucleotides (ODNs) are a class of therapeutic agents that can be used for antisense, RNA interference, immunorecognition and aptamer binding.[1,2,3] many ODN analogs have been developed for biological applications, none are completely satisfactory and further improvements in certain properties are required before the full therapeutic value of these molecules can be realized
We found that uptake of a triazolyl-phosphonate DNA analogs (TP ODNs) was not significantly improved during cell division, but bright TP ODN granules were observed at the cell membrane immediately before division, and at the splitting junction after division (Figure 6)
A general problem associated with studying the efficacy of various modified oligonucleotides in cell culture relates to their uptake and activity
Summary
Oligodeoxynucleotides (ODNs) are a class of therapeutic agents that can be used for antisense, RNA interference, immunorecognition and aptamer binding.[1,2,3] many ODN analogs have been developed for biological applications, none are completely satisfactory and further improvements in certain properties are required before the full therapeutic value of these molecules can be realized. Properties to be considered are stability, cellular uptake efficiency, site-specific delivery and offtarget effects. Triazolylphosphonate DNA analogs can be synthesized efficiently on a solid support and undergo endocytosis by multiple cell types in vitro in the absence of transfection lipids.[4] To further neutralize anionic DNA and improve the cellular uptake of these analogs, we have extended this modification to more positively charged, peptide-substituted 1,2,3-triazolyl-phosphonate DNA analogs (TP ODNs). The precise charge and location of these modifications can be fine-tuned by structural variations
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