Abstract
Deficient stability towards nuclease-mediated degradation is one of the most relevant tasks in the development of oligonucleotide-derived biomedical agents. This hurdle can be overcome through modifications to the native oligonucleotide backbone structure, with the goal of simultaneously retaining the unique hybridization properties of nucleic acids. The nucleosyl amino acid (NAA)-modification is a recently introduced artificial cationic backbone linkage. Partially zwitterionic NAA-modified oligonucleotides had previously shown hybridization with DNA strands with retained base-pairing fidelity. In this study, we report the significantly enhanced stability of NAA-modified oligonucleotides towards 3′- and 5′-exonuclease-mediated degradation as well as in complex biological media such as human plasma and whole cell lysate. This demonstrates the potential versatility of the NAA-motif as a backbone modification for the development of biomedically active oligonucleotide analogues.
Highlights
As they efficiently modulate biological processes, oligonucleotides hold immense potential to serve as scaffolds for novel pharmaceutical agents
Based on literature precedent [39,40,41], two exonucleases commonly employed to test the stability of DNA oligonucleotides were chosen: the 30 →50 exonuclease snake venom phosphodiesterase (SVP) from Crotalus adamanteus and the 50 →30 exonuclease bovine spleen phosphodiesterase (BSP), respectively
23, x with one of the two exonucleases, the assay mixtures were analyzed by denaturing polyacrylamide oligonucleotide(PAGE)
Summary
As they efficiently modulate biological processes, oligonucleotides hold immense potential to serve as scaffolds for novel pharmaceutical agents. Due to their sequence-specific hybridization to DNA duplexes or single-stranded mRNA, single-stranded exogenous oligonucleotides can display antigene or antisense activity, respectively. Exogenous double-stranded RNA (siRNA) can regulate gene expression via the RNA interference mechanism [1]. The high polarity of native nucleic acid structures is a major disadvantage with these approaches. The oligoanionic phosphate diester-linked backbone significantly hampers cellular uptake and accounts for an overall poor pharmacokinetic profile. The phosphate-sugar backbone is prone to nuclease-mediated cleavage, further preventing applications in vivo
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