Abstract
Background: Despite recent advances, major hurdles still need to be cleared for widespread application of therapeutic antisense technologies. In particular, pharmacokinetic properties and efficient cellular uptake need to be improved through chemical derivatization or bioconjugation. Results: The 2′-O-thioethylene nucleotide building block affords easy implementation into standard oligonucleotide synthesis protocols and was used to attach oligolysine chains to phosphodiester oligonucleotides by direct reaction with S-sulfonate protected peptides. Efficient gene silencing was induced in a cell culture model after transfection reagent-free application of the conjugates. Conclusion: A facile optimized procedure for generating oligonucleotide–peptide conjugates was established. The attachment of short basic peptides via a labile linker is sufficient to enhance membrane permeability of oligonucleotides and result in successful gene silencing.
Acknowledgements
The authors would like to thank Martina Köberl and Sandra Haselmaier-Auernigg for support with mass spectrometric analyses.
Financial & competing interests disclosure
A patent application comprising some of the described methodology and structures has been filed. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.