An efficient biodelivery system for antisense polyamide nucleic acid (PNA).

Oligonucleotides
Mohamed MehiriNadia Patino

Abstract

With the aim of developing a general and straightforward procedure for the intracellular delivery of naked peptide nucleic acids (PNAs), we designed an intracellularly biodegradable triphenylphosphonium (TPP) cation based transporter system. In this system, TPP is linked, via a biolabile disulfide bridge, to an activated mercaptoethoxycarbonyl moiety, allowing its direct coupling to the N-terminal extremity of a free PNA through a carbamate bond. We found that such TPP-PNA-carbamate conjugates were highly stable in a cell culture medium containing fetal calf serum. In a glutathione-containing medium mimicking the cytosol, the conjugates were rapidly degraded into an unstable intermediate, which spontaneously decomposed, releasing the free PNA. Using a fluorescence-labeled PNA-TPP conjugate, we demonstrated that conjugates were taken up by cells. Efficient cellular uptake and release of the PNA into the cytosol was further confirmed by the anti-HIV activity measured for the TPP-conjugate of a 16-mer PNA targeting the TAR region of the HIV-1 genome. This conjugate exhibited an IC(50) value of 1 microM, while the free 16-mer PNA did not inhibit replication of HIV in the same cellular test.

References

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Citations

Sep 24, 2010·Chemical Communications : Chem Comm·Maria DucaGiovanna Barbarella
Oct 3, 2012·Journal of Nucleic Acids·Gregory UpertNadia Patino
Jun 19, 2009·Expert Opinion on Biological Therapy·Virendra N PandeyBinay Chaubey
Jun 1, 2012·Expert Opinion on Drug Discovery·Ravinder Malik, Ipsita Roy
Sep 20, 2012·Journal of Nucleic Acids·Eriks Rozners
Oct 25, 2016·Pharmacology & Therapeutics·Sterghios A MoschosMark A Lindsay
Jun 21, 2014·Bioconjugate Chemistry·Kelsey R BeaversCraig L Duvall
Mar 10, 2018·Beilstein Journal of Organic Chemistry·Françoise DebartJean-Jacques Vasseur
Jan 9, 2020·Bioorganic Chemistry·Anna R StasińskaMarcin K Chmielewski
Aug 10, 2021·Beilstein Journal of Organic Chemistry·Nikita BrodyaginEriks Rozners

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