TY - JOUR
T1 - Cellular Antisense Activity of PNA-Oligo(bicycloguanidinium) Conjugates forming Self-Assembled Nano-aggregates
AU - Valero, Julian
AU - Shiraishi, Takehiko
AU - de Mendoza, Javier
AU - Nielsen, Peter Eigil
N1 - © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2015/7/1
Y1 - 2015/7/1
N2 - A series of peptide nucleic acid-oligo(bicycloguanidinium) (PNA-BGn) conjugates were synthesized and characterized in terms of cellular antisense activity by using the pLuc750HeLa cell splice correction assay. PNA-BG4 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 μM, 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-BG4 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.
AB - A series of peptide nucleic acid-oligo(bicycloguanidinium) (PNA-BGn) conjugates were synthesized and characterized in terms of cellular antisense activity by using the pLuc750HeLa cell splice correction assay. PNA-BG4 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 μM, 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-BG4 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.
U2 - 10.1002/cbic.201500172
DO - 10.1002/cbic.201500172
M3 - Journal article
C2 - 26010253
SN - 1439-4227
VL - 16
SP - 1593
EP - 1600
JO - ChemBioChem
JF - ChemBioChem
IS - 11
ER -