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Cellular Antisense Activity of PNA–Oligo(bicycloguanidinium) Conjugates Forming Self‐Assembled Nanoaggregates
Author(s) -
Valero Julián,
Shiraishi Takehiko,
de Mendoza Javier,
Nielsen Peter E.
Publication year - 2015
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201500172
Subject(s) - conjugate , chemistry , peptide nucleic acid , peptide , nucleic acid , cooperativity , biophysics , biological activity , in vivo , biochemistry , in vitro , biology , mathematical analysis , mathematics , microbiology and biotechnology
A series of peptide nucleic acid–oligo(bicycloguanidinium) (PNA–BG n ) conjugates were synthesized and characterized in terms of cellular antisense activity by using the pLuc750HeLa cell splice correction assay. PNA–BG 4 conjugates exhibited low micromolar antisense activity, and their cellular activity required the presence of a hydrophobic silyl terminal protecting group on the oligo(BG) ligand and a minimum of four guanidinium units. Surprisingly, a nonlinear dose–response with an activity threshold around 3–4 μ M , indicative of large cooperativity, was observed. Supported by light scattering and electron microscopy analyses, we propose that the activity, and thus cellular delivery, of these lipo‐PNA–BG 4 conjugates is dependent on self‐assembled nanoaggregates. Finally, cellular activity was enhanced by the presence of serum. Therefore we conclude that the lipo‐BG‐PNA conjugates exhibit an unexpected mechanism for cell delivery and are of interest for further in vivo studies.